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6.1.2. loperamide dose adjustment

Patients are expected to take loperamide prophylaxis as directed. However, patients may require individualization of loperamide prophylaxis dose (up to a maximum dose of 16 mg per day) with the goal of titrating to 1-2 bowel movements a day.  
- Diarrhea  
− For patients who develop diarrhea during Cycle 1, loperamide should be increased up to a maximum of 16 mg a day.  
- Constipation
− If a patient is unable to tolerate loperamide due to symptomatic constipation, loperamide should be held until after the first bowel movement and then resumed at a dose reduced by one level.  
− For recurrent symptomatic constipation events, hold loperamide until after the first bowel movement and then resume at a dose reduced to the next lower dose level.  
− If a patient is unable to tolerate once-daily loperamide due to constipation, hold loperamide and discuss subsequent loperamide dosing with the Medical Monitor.  
− Neratinib dosing should continue if loperamide is held.
Recommended dose reductions for constipation due to loperamide are listed in Table 17.  
| Dose Level                                                                 | Loperamide Dose   | Tablets/Capsules per Day   |
|----------------------------------------------------------------------------|-------------------|----------------------------|
| 0                                                                          | 4 mg TID          | 6 tablets/capsules a day   |
| -1                                                                         | 4 mg BID          | 4 tablets/capsules a day   |
| -2                                                                         | 2 mg TID          | 3 tablets/capsules a day   |
| -3                                                                         | 2 mg BID          | 2 tablets/capsules a day   |
| -4                                                                         | 2 mg once a day   | 1 tablet/capsule a day     |
| Abbreviations: BID = twice daily; mg = milligrams; TID = three times daily |                   |                            |
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6.1.2.1. loperamide antidiarrheal therapy

The Investigator must review with the patient the **Patient Instructions** for the management of diarrhea and the **Patient Diary** for the patient's daily recording of IP dose, any adverse reactions, the number of stools, and the use of loperamide and/or other antidiarrheals. A copy of the Patient Instructions are to be handed to the patient before leaving the site with IP on or before the first day on neratinib, with clear instructions to contact the Investigator in the event of de novo onset or persistent Grade ≥2 diarrhea to discuss the appropriate course of treatment. Documentation of the number of stools at baseline should be captured in the patient's record. Any occurrences of loose stools, diarrhea or constipation must be documented by the patient as precisely as possible and captured in the Patient Diary. The entries in the Patient Diary should be reviewed by the study staff together with the patient at the end of the first month of neratinib therapy.  
The **Patient Diary** will contain details of the daily number of unformed stools the patient has experienced since the last visit. Documenting the toxicity grade of the diarrhea or constipation by the study staff needs to be reported accurately on the Case Report Form (CRF) using an adjusted NCI CTCAE version 4.0 criteria (see Section 5.2). Also, the daily dose of loperamide (or other antidiarrheals, if applicable) noted on the diary will be reviewed and recorded on the CRF. Loperamide will be provided and dispensed directly by the site on or before C1D1 with neratinib. It is very important to initiate treatment with loperamide concomitantly with the first dose of neratinib to minimize the occurrence and severity of diarrhea.
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prophylactic dosing instructions (cycles 1

- Inform patients that they will experience diarrhea while taking neratinib.  
- Administer loperamide: 4 mg TID for the first 14 days, with the first dose administered concomitantly with the first dose of neratinib. After two weeks, take loperamide 4 mg BID until the end of the second cycle of therapy regardless of whether the patient is experiencing diarrhea or not.  
- For patients with persistent Grade 1 diarrhea (<4 stools per day above baseline) on loperamide, increase loperamide up to 16mg daily (4 mg four times a day [QID]).  
Lomotil® (diphenoxylate hydrochloride and atropine sulfate) 1 tablet (2.5 mg) every 6 to 8 hours may be added (or equivalent as approved by Sponsor).  
- For Grade 2 diarrhea during Cycle 1 (4 to 6 stools per day above baseline, despite intensive anti-diarrheal therapy), consider adding octreotide (short-acting) 150 µg subcutaneous [SC] injection 3 times a day, or after initial dose of short-acting octreotide, if well tolerated, a single dose of octreotide LAR 20 mg by IM injection (equivalent medication may be used with approval of the Sponsor).  
- The sites must contact the patient by phone 1 day, 2 days, and 3 days after the first dose of neratinib in Cycle 1 to inquire about any diarrhea and ensure the patient is compliant with anti-diarrheal therapy.
(**These phone calls are mandatory and must be recorded in the study chart**
together with response from the patient and action taken.)  
- Instruct patients to promptly report diarrhea symptoms. - Instruct patient to record on the Patient Diary the number of stools per day and the dose of any anti-diarrheal medication taken each day for the first cycle of therapy (see Section 5). Patients must record all doses of neratinib for the entire duration of the study.
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for new onset uncomplicated grade

Dietetic measures
- Stop all lactose-containing products.  
- Drink 8 to 10 large glasses of clear liquids per day. - Eat frequent small meals.  
- Recommend a low-fat regimen enriched with bananas, rice, applesauce and toast until the resolution of diarrhea.
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pharmacological treatment

- Administer loperamide: initial dose of 4 mg (2 tablets/capsules) with the first bout of diarrhea followed by 2 mg (1 tablet or capsule) every 4 hours or after every unformed stool (maximum 16 mg a day) and continue loperamide at this frequency until diarrhea-free for 12 hours.  
- For patients with persistent Grade 1 diarrhea on loperamide, increase loperamide up to 16 mg (4 mg QID) and Lomotil (diphenoxylate hydrochloride and atropine sulfate) 1 tablet (2.5 mg) every 6 hours to 8 hours may be added (or equivalent as approved by the Sponsor).  
- For Grade 2 diarrhea (4 to 6 stools per day above baseline, despite intensive antidiarrheal therapy), consider adding octreotide (short-acting) 150 µg SC TID; or after initial dose of short-acting octreotide, if well tolerated, a single dose of octreotide LAR 20 mg IM (equivalent medication may be used with approval of the Sponsor).
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for grade 3 or grade

- Administer loperamide: initial dose of 4 mg (2 tablets or capsules) with the first bout of diarrhea followed by 2 mg (1 tablet or capsule) every 4 hours or after every unformed stool (maximum 16 mg a day) and continue loperamide at this frequency until diarrhea-free for 12 hours. Then titrate the amount of loperamide used to keep diarrhea controlled (<4 stools/ day).  
- For patients with Grade 3-4 diarrhea on loperamide, consider administration of Lomotil (diphenoxylate hydrochloride and atropine sulfate) 1 tablet (2.5 mg) every 6 hours to 8 hours may be added (or equivalent as approved by the Sponsor).  
- Administer octreotide (100 to150 µg SC BID or IV (25 to 50 µg/h) if dehydration is severe, with dose escalation up to 500 µg SC TID.  
- Use IV fluids as appropriate.  
- Consider prophylactic antibiotics as needed (eg, fluoroquinolones) especially if diarrhea is persistent beyond 24 hours or there is fever or Grade 3 to4 neutropenia.
Stool cultures should be done to exclude infectious causes of Grade 3 or 4 diarrhea or diarrhea of any grade with complicating features (dehydration, fever, and/or Grade 3 or 4 neutropenia) per the Investigator's discretion. Results from occult blood, fecal leukocyte stain, Clostridium difficile, Campylobacter, Salmonella, and *Shigella* testing, when performed, should be reported using the appropriate CRF. Patients with significant diarrhea who are unresponsive to medical treatment may require treatment interruption and/or dose reduction.
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6.2. permitted concomitant treatment

Any palliative and/or supportive care for cancer-related symptoms, which are not otherwise specified in the list of prohibited medications (Section 6.3), or drugs with potential for drug-drug interactions (Section 6.4), or in the associated Appendices 3 (cytochrome P450 inhibitors and inducers), 4 (p-glycoprotein substrates and inhibitors) and 5 (drugs associated with QT/QTc prolongation), is permitted at the Investigator's discretion. Specifically, the following treatments are permitted during the study:  
- Standard therapies for preexisting medical conditions, medical and/or surgical complications, and palliation. All medication(s) as well as previous hormonal therapy, dose and length of therapy should be recorded in the CRF.
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- bisphosphonates and receptor activator

ligand inhibitors (eg, denosumab), regardless of indication, provided patients have been on stable doses for at least 2 weeks prior to enrollment. The stable dose should be maintained during the IP treatment period. Patients requiring initiation of bisphosphonate treatment during the course of the study should be discontinued due to progressive disease (PD), unless disease progression can be completely ruled out and clearly documented in the patient's source documentation.  
- **Secondary prophylactic use of growth factors** (eg, granulocyte colony-stimulating factor or granulocyte macrophage colony-stimulating factor) may be implemented per the currently applicable ASCO and the European Organization for Research and Treatment of Cancer (EORTC) (Aapro et al, 2011) guidelines at the Investigator's discretion, if significant neutropenia or febrile neutropenia/infection is observed.
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6.3. prohibited concomitant treatment

The following treatments are prohibited throughout the duration of the active (treatment) phase of the study: Other than as specified in protocol, any concurrent chemotherapy, radiotherapy (including palliative radiotherapy), surgery related to cancer, anticancer immunotherapy, or other anticancer treatments including other investigational agents are prohibited. Megestrol®, bisphosphonates, and RANK-ligand inhibitors are permitted provided the patient has been on a stable dose for at least 2 weeks prior to the start of neratinib. Patients with breast cancer on a stable dose of hormonal therapy will be permitted to remain on this regimen through their participation in the study.
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6.4. potential for drug-drug interactions

Patients should avoid agents known to be strong cytochrome P450 (CYP) 3A4 inducers or inhibitors (eg, ketoconazole) for the duration of the active phase of the study. Patients should also avoid grapefruit and herbal remedies, including St John's Wort. Refer to Appendix 3 for a list of inhibitors and inducers of CYP isoenzymes. If unavoidable, patients taking such agents should be monitored closely. Patients taking digoxin, a P-glycoprotein (P-gp) substrate with a narrow therapeutic window, should be monitored closely. The digoxin dose should be adjusted as needed, since neratinib is an inhibitor of P-gp. Co-administration of neratinib with digoxin could result in increased digoxin levels and associated digoxin toxicity. Refer to Appendix 4 for a list of substrates and inhibitors of P-gp.  
Patients using drugs known to cause QT/QTc prolongation should be monitored closely with serial electrocardiograms (ECG) at the Investigator's discretion. Refer to Appendix 5 for a summary of drugs known to have a risk of causing QT/QTc prolongation, potentially causing TdP. Patients taking oral coumarin-derivative anticoagulants (eg, warfarin and phenprocoumon) should be monitored closely and their anticoagulant dose adjusted as needed. 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. It has been observed that a single 240-mg dose of neratinib combined with lansoprazole may decrease neratinib AUC by up to 70%. It is unknown whether separating PPI and neratinib doses reduces the interaction. If an H2-receptor antagonist such as ranitidine is required, neratinib should be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist. If antacids are necessary, the antacid dose and the neratinib dose should be separated by 2 to 4 hours.
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7. study assessments 7.1. efficacy

For cohorts receiving combination treatment that includes trastuzumab (Table 2 and Table 3), 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
(Appendix 1 Table A1.1 and Table A1.2). For all other cohorts not receiving trastuzumab (Table 4 and Table 5), post-treatment disease assessment will be conducted at the beginning of Week 9 (ORRfirst), and every 2 cycles (± 7 days) thereafter (Appendix 1 Table A1.1 and 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. For patients who enrolled prior to Amendment 6, the same method of measurement (eg PET/CT) and same method of disease assessment (eg metabolic response by PET Response Criteria) should continue through final assessments
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7.1.1. tumor assessments

Radiographic tumor assessments use CT (or MRI or PET/CT) and tumor markers will be performed in accordance with the Schedule of Procedures (Appendix 1 Table A1.1 and Table A1.2). Following one year on therapy, scans may move to every 4 cycles for trastuzumabcontaining 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.
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7.1.1.1. general information

All target and nontarget sites of disease (see Appendix 6) identified at screening must be followed for the duration of the study. Their size, presence, and absence should be noted throughout follow-up. Overall response for each patient is based on the combined results for target and nontarget lesions and the presence or absence of new lesions.  
Tumor-based efficacy endpoints (ie, PFS, ORRfirst, and confirmed ORR) will be based on tumor assessments performed by the Investigator. Response and progression will be evaluated using RECIST version 1.1 (see Appendix 6). Tumor assessments will be performed for all patients as described in Section 7.1 and in (Appendix 1 Table A1.1 and Table A1.2) throughout the treatment phase until the occurrence of documented disease progression, death or patient withdrawal from the study (ie, lost to follow-up, withdrawal of consent), whichever occurs first (refer to Section 9 for a complete list of reasons for withdrawal from the study). Additional tumor evaluations may be performed as clinically indicated. Missed tumor assessments must be performed as soon as possible. As soon as evaluations for each tumor assessment are completed, the Investigator should assess the patient's overall response (target and nontarget lesions) based on appropriate disease response criteria and overall response algorithms (see Appendix 6). Scans must be assessable for all evaluations.  
The longest diameters (LD) for all target lesions will be recorded (short axis for target pathological lymph nodes) within the source documentation. The LD for all target lesions will be added and reported as the baseline sum LD (SLD). Per RECIST version 1.1, for determining CR or PR, all post-baseline tumor measurements will be compared with the baseline SLD; for determining PD, the post-baseline measurement is compared with the smallest SLD recorded since initiation of treatment, including baseline (Appendix 6). Patients who discontinue study treatment and do not have PD will be asked to remain on study for tumor evaluation per protocol and for determination of progression free survival (PFS; see Section 8.3).
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7.1.1.2. radiographic/imaging evaluations

The same method of measurement (eg, CT or MRI) and the same technique of assessment should be used to characterize each identified and reported lesion at baseline through the final visit. All measurements should be taken, recorded, and measured on computer screens of Picture Archival Communication (PAC) systems or on hard-copy images using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of the active drug phase and never more than 28 days before the beginning of the active drug phase. As often as possible, lesions should be assessed by the same Investigator or same radiologist using the same method of measurement. Physical examination may not be the sole method of assessment for a solitary lesion. For patients with measurable and evaluable skin lesions, photographs should be taken, inclusive of a ruler. All patients must have a CT of the chest, abdomen and pelvis at baseline. Additional areas of assessment at baseline would include additional possible target or non-target lesion. On-study scans should be repeated at the appropriate interval for areas with known target or non-target disease. Additional fields of imaging should be repeated as clinically indicated. Patients with a history of brain metastasis must receive a Brain MRI or CT at baseline. Follow-up Brain MRI or CT scans should only be completed as clinically indicated. Definitions of measurable disease and measurable lesions, documentation of "target" and "nontarget" lesions, and evaluation of response are summarized in Appendix 6 (Eisenhauer, et al, 2009). Baseline screening radiographic studies and all subsequent radiographic studies and their associated reports will be collected and stored by the Sponsor for possible future independent review.
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7.1.2. tumor assessments - clinical

Clinical examination should include caliper measurement when lesions are superficial. Lesions that cannot be measured with calipers should be recorded as non-measurable. Documentation by color photography in good light and including a ruler to estimate the size of the lesion is required. Note that when lesions can be evaluated by clinical examination and imaging, imaging evaluation should be undertaken by CT or MRI as appropriate.
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7.1.3. quality of life assessments

Patient reported outcomes using the FACT-G (Appendix 8) assessment will be performed at screening, C1D1, and at the beginning of each cycle (per office visit, prior to drug administration) for up to 6 months or end of treatment, whichever comes first.
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7.1.4. ecog performance status

The ECOG performance status will be assessed in accordance with the Schedule of Procedures (Appendix 1 Table A1.1 and Table A1.2). The ECOG categories are summarized in Appendix 2.
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7.2. safety assessments

Refer to the Schedule of Procedures (Appendix 1 Table A1.1 and Table A1.2) for time points. The following safety endpoints will be assessed: Medical history, AEs, vital signs, detailed/brief (system-guided) physical examinations, 12-lead ECGs, LVEF (via ECHO or MUGA), and laboratory evaluations. AEs will be graded according to the NCI CTCAE version 4.0. SAEs will be reported until 28 days after the last dose of IP(s) and will be followed until resolution. Should an Investigator be made aware of any SAEs occurring any time after the reporting period that may be causally related to the administration of neratinib, it should be promptly reported. More details on AEs can be found in Section 12. The diary used for recording of IP intake will also be used by patients to document any other study treatment. In case of diarrhea, the diary also serves to document the number of loose stools per day and use of loperamide/other antidiarrheal treatments taken.
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7.2.1. laboratory assessments

Laboratory testing will be performed in accordance with the Schedule of Procedures (Appendix 1 Table A1.1 and Table A1.2). The institutional laboratory will analyze all hematology, routine blood chemistry, and urine samples collected. Samples will be analyzed at a facility meeting Good Laboratory Practice (GLP) requirements as evidenced by current accreditation by an independent testing organization. Laboratory assessments are not required on C1D1 if previously obtained within 72 hours prior to C1D1 as part of screening, with no clinically significant findings. The following laboratory parameters will be determined, as summarized in Table 18.  
| Hematology:                                                                          | Hematocrit (Hct) Hemoglobin (Hb) Platelet count Red blood cell (RBC) count White blood cell (WBC) count, with differential                                                |                                                                                                                                         |
|--------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|
| Clinical chemistry:                                                                  | Albumin  Alkaline phosphatase  Alanine transaminase (ALT) Aspartate transaminase (AST) Blood urea nitrogen (BUN) Calcium Chloride  Serum Creatinine Glucose (non-fasting) | Lactate dehydrogenase (LDH) Magnesium Phosphorus Potassium  Serum total cholesterol (non-fasting) Sodium  Total bilirubin Total protein |
| Urinalysis (dipstick or laboratory  analysis; microscopic  examination if abnormal): | Blood Protein Glucose                                                                                                                                                     |                                                                                                                                         |
| Serum or urine pregnancy test:                                                       | In women of child-bearing capacity (at screening and repeated only if  performed outside 72 hours of C1D1).                                                               |                                                                                                                                         |  
All clinically important abnormal laboratory tests occurring during the study will be repeated at appropriate intervals until they return either to baseline or to a level deemed acceptable by the Investigator and/or the Sponsor Medical Monitor (or his/her designated representative), or until a diagnosis that explains them is made. Criteria for reporting abnormal laboratory values as AEs are summarized in Section 12.1.2. For all laboratory values that are outside of the laboratory's reference range, the Investigator (or designee) must record CS (clinically significant) or NCS (not clinically significant) on the laboratory sheet.
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7.2.2. vital signs

The following vital signs will be assessed in accordance with the Schedule of Procedures (Appendix 1 Table A1.1 and Table A1.2):
- Blood pressure (systolic and diastolic; mmHg)  
- Resting heart rate (beats per minute)
- Respiration rate (breaths per minute).  
- Body temperature (°C)
- Weight (kg)
- Height, cm (Screening only)
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7.2.3. physical examinations

Physical examinations will be performed in accordance with the Schedule of Procedures (Appendix 1 Table A1.1 and Table A1.2). The detailed/brief (system-guided) physical examination will evaluate any clinically significant abnormalities; including worsening of medical history conditions.
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7.2.4. electrocardiograms

Single standard 12-lead digital ECGs will be performed in accordance with the Schedule of Procedures (Appendix 1 Table A1.1 and Table A1.2).  
- For the baseline assessment, ECG will be performed within 14 days prior to C1D1 for all cohorts. Patients will have ECGs performed only at baseline and at end of treatment.
The ECG will include heart rate, rhythm and RR, PR, QRS, and QTc intervals. The ECG will be read and interpreted at the investigational site for patient safety monitoring, and documentation stored with the source documents. Each ECG will be reviewed by the Investigator or delegate who will document this review by his/her initials and date. The Investigator (or delegate) will record CS (clinically significant) or NCS (not clinically significant) on each non-normal ECG.
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7.2.5. left ventricular ejection fraction

The MUGA scan or ECHO scan to determine LVEF will be performed in accordance with the Schedule of Procedures (Appendix 1 Table A1.1 and Table A1.2).  
- The Screening MUGA/ECHO scans to determine LVEF will be performed as routine procedures within 28 days before C1D1.  
- For any cohort treated with trastuzumab (Table 2 and Table 3): following Screening, MUGA/ECHO scans will be performed every 12 weeks (+/- 7 days) and at end of treatment.  
- For all other cohorts not receiving trastuzumab (Table 4 and Table 5): MUGA/ECHO
scans will be performed at screening and at end of treatment.
It is strongly recommended to use the same method of cardiac evaluation (ECHO or MUGA) at each time point for each patient.
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7.2.6. archival and fresh tumor

Biospecimen collections will be performed in accordance with the Schedule of Procedures (Appendix 1 Table A1.1 and Table A1.2). All specimens should be processed, packaged and shipped according to the Laboratory Manual. Archival and/or Fresh Tumor Tissue:
All efforts will be made to collect archival and/or fresh pretreatment (screening) tumor tissues (except for breast cancer and NSCLC cohorts where collection of a pretreatment biopsy is mandatory), and, if possible, upon disease progression for analysis as outlined in the Exploratory Objectives of the protocol.
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whole blood for germline dna

Blood will be obtained during the study (preferably acquired during screening, at the same time as hematology, serum chemistry, and plasma samples are taken).
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plasma for biomarker analysis of

Serial plasma samples for subsequent exploratory biomarker analyses will be collected from each patient during the 3 phases of the study:  
1. Pretreatment (preferably acquired during screening, or at the latest on C1D1 but **before**
the patient takes their first neratinib monotherapy or combination therapy),
2. On-treatment and 3. Post-treatment (coordinated with EOT).
It is expected that these banked plasma specimens will subsequently be used for cfDNA mutational analysis to investigate mechanisms of primary and/or acquired resistance to neratinib therapy.
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7.3. protocol deviations

Protocol deviations should be reported to the Sponsor (or designee) as they occur or are discovered.
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7.4. patient diary

A Patient Diary will be provided by the Investigator for the patient to record daily intake of neratinib for every cycle, loperamide (and/or other antidiarrheal medication) only for the first two cycles of treatment and the frequency of diarrhea.
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8. study conduct

Schedule of Procedures is provided in (Appendix 1 Table A1.1 and Table A1.2). In addition to the procedures listed in this section, unscheduled clinic visits and procedures should be performed at the Investigator's discretion to assess symptoms and concerns newly reported by the patient to rule out or confirm potential recurrence, or for the purpose of assessing the patient's safety.
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8.1. informed consent

Before any study procedures are performed, obtain informed consent, as required by the IRBs/ECs and regulatory authorities.
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8.2. screening all cohorts

Screening activities are to be conducted within 14 days prior to C1D1, except for CT, PET/CT or MRI disease assessment (within 28 days prior to C1D1), ECHO/MUGA (within 28 days prior to C1D1), a serum or urine pregnancy test (at screening, and to be repeated if performed outside 72 hours of C1D1). In breast cancer and NSCLC patients, fresh tumor biopsy should be obtained within 28 days prior to C1D1 and for all other cohorts, archival and/or fresh pretreatment tumor tissue should be obtained during screening or within the first cycle of treatment. The following information/assessments will be collected/recorded at Screening:
- Medical history:  
− Presence of chronic conditions and/or medical history of significance (include review of history of cardiac, pulmonary, and gastrointestinal disease) including smoking history (only for NSCLC patients), relevant surgical procedures, or symptoms experienced during the previous 30 days and those ongoing at the time of screening, and any medical conditions that require medication. Identify start of current medical conditions by at least a year.  
− Cancer history, including but not limited to, date of first diagnosis, nodal status
(based on pathologic assessment of nodes at the time of surgery, either before adjuvant chemotherapy or after completion of neoadjuvant chemotherapy), histology, tumor stage at diagnosis, previous chemotherapy/ biotherapy/immunotherapy, previous adjuvant therapy, drug names, start and stop dates, reason for treatment discontinuation, previous radiation, and prior cancer related surgical therapies.  
− Other previous and concomitant medication will be documented, as described in Section 6.  
- Demography: date of birth, sex, race (Asian, Black or African American, White, Other).  
- Physical examination. Refer to Section 7.2.3.  
- Vital signs, including height and weight. Refer to Section 7.2.2.  
- ECG. Refer to Section 7.2.4.  
- ECHO or MUGA (to obtain LVEF). Refer to Section 7.2.5. - Laboratory tests (hematology and serum chemistry, urine test by dipstick or laboratory analysis, urine or serum pregnancy in women of child-bearing capacity [at screening and repeated on C1D1 prior to treatment if performed >72 hours prior to C1D1]). Refer to Section 7.2.1.  
- Archival and/or fresh tumor tissue sample and whole blood collection from all patients for centralized *ERBB* mutation and amplification. Refer to Section 7.2.6.  
- Baseline pretreatment plasma sample for exploratory biomarker analysis. Refer to Section 7.2.6.  
- Whole blood DNA sample for exploratory biomarker analysis. Refer to Section 7.2.6. - Quality of Life Assessments. Refer to Section 7.1.3.  
- ECOG performance status. Refer to Section 7.1.4. - Radiographic tumor assessment within 28 days prior to C1D1. Refer to Section 7.1.1.
The C1D1 physical examination, ECOG performance status, and laboratory tests may be omitted if the screening values were obtained within 72 hours prior to initiation of treatment.
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8.2.1. active treatment stage

For patients enrolled to a neratinib containing cohort, neratinib will be self-administered by patients daily. For study cohorts where neratinib will be administered in combination with another therapy, combination treatment will consist of neratinib plus trastuzumab, and neratinib plus fulvestrant plus trastuzumab at dose regimens and cycle lengths described in Section 5, and in accordance with the Schedule of Procedures provided in (Appendix 1 Table A1.1 and Table A1.2). In the study cohorts where single agent fulvestrant or fulvestrant plus trastuzumab will be administered at dose regimens and cycle lengths described in Section 5, and in accordance with the Schedule of Procedures provided in (Appendix 1 Table A1.1 and Table A1.2).  
The following will be performed in accordance with the Schedule of Procedures provided in
(Appendix 1 Table A1.1 and Table A1.2):  
- Physical examination. Refer to Section 7.2.3. - Vital signs and weight. Refer to Section 7.2.2. - Laboratory tests. Refer to Section 7.2.1. - ECOG performance status. Refer to Section 7.1.4. - Radiographic tumor assessment. Refer to Section 7.1.1.  
- Plasma sample for exploratory biomarker analyses. Refer to Section 7.2.6.  
- Treatment compliance assessment. Refer to Section 7.4.  
- Review compliance with loperamide antidiarrheal therapy. Refer to Section 6.1.  
- AE assessment. Refer to Section 12.
- Concomitant medication assessment. Refer to Section 6.  
- Dispense and collect IP. Refer to Section 5.4.  
- ECG. Refer to Section 7.2.4.  
- ECHO or MUGA (to obtain LVEF). Refer to Section 7.2.5.  
- Health Outcomes Assessment. Refer to Section 7.1.3.
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8.2.2. end of treatment visit

After the end of treatment (EOT), the following assessments should be scheduled 28 days (+14 days) after the last dose of IP(s), in accordance with the Schedule of Procedures in (see Table A1.1 and Table A1.2). If the patient is unable or unwilling to undergo any assessment, the last assessment on record will be used as end of treatment assessment.  
- Physical examination. Refer to Section 7.2.3.  
- Vital signs, including weight. Refer to Section 7.2.2. - ECG. Refer to Section 7.2.4. ECHO or MUGA (obtain LVEF). Refer to Section 7.2.5.  
- Laboratory tests (hematology, chemistry). Refer to Section 7.2.1.  
- Plasma sample for exploratory biomarker analyses. Refer to Section 7.2.6. - Radiographic tumor and response assessment should be collected for patients discontinuing treatment for any reason other than radiological disease progression. Refer to Section 7.1.1.  
- AE assessment. Refer to Section 12.  
- Concomitant medication assessment. Refer to Section 6.  
- Treatment compliance assessment. Refer to Section 5.4. - Optional tumor biopsy. Refer to Section 7.2.6 .
Patients will enter the Follow-up Stage after these EOT assessments.
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8.3. long-term follow-up for all

After the end of treatment, patients who do not withdraw consent will enter the long-term Follow-up Stage. These patients will be followed for PFS and survival status during the long-term follow-up phase. The following will be performed in accordance with the Schedule of Procedures (Appendix 1 Table A1.1 and Table A1.2):
- Continue to monitor AEs until the 28th day after the last dose of IP(s).  
- Anti-cancer medications taken since last contact.  
- For patients who discontinued treatment for any reason other than disease progression, collect radiographic tumor and response assessments until documented disease progression, death or withdraw of consent. Refer to Section 7.1.1.  
- After disease progression, follow patients via clinic visits, email or phone calls every 12 weeks (±14 days) after each patient's last dose of treatment. Patients who received trastuzumab will continue cardiac monitoring with ECHO or MUGA scanning every 6 months up to 24 months after the last dose of trastuzumab.  
- If a patient withdraws from the follow-up portion of the study, the primary reason for discontinuation should be documented (see Section 9.3).
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8.4. end of study

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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9. patient withdrawal and replacement

Patients **must** be discontinued from the **investigational products** (but may remain in the study for long term follow up, if appropriate), under the following circumstances listed in this section and in Section 5.2, unless otherwise agreed with the Medical Monitor:
- If the patient requires more than 2 dose reductions of IP (see Section 5.2).  
- If the IP is withheld due to a neratinib-related AE for >28 days. Patients who are clinically benefiting from therapy with neratinib may be resumed on therapy after 28 days if approved in advance by the Sponsor.  
- Disease progression. Patients who, in the opinion of the Investigator, are continuing to benefit from neratinib despite disease progression may continue to receive neratinib if approved in advance by the Sponsor. Patients who are initially enrolled to a non-neratinib containing arm may remain on study and receive neratinib, fulvestrant and trastuzumab at the time that the local investigator determines the patient has unequivocal evidence of disease progression as documented by imaging, clinical examination, or disease related symptoms before the first scan post-treatment.  
- Pregnancy (see Section 12.4). - Investigator request. - Patient request (ie, withdrawal of consent for treatment).
Withdrawal due to AE should be distinguished from withdrawal due to other causes and recorded on the appropriate AE case report form (CRF) page. In the case of the following events, the patient should discontinue treatment, but should be asked to remain on study for response assessment as well as PFS if the event leading to discontinuation of treatment occurs prior to the first post-baseline tumor assessment, or for response assessment, PFS, and OS if the event occurs after the first tumor evaluation:
- Adverse events/toxicity  
- Symptomatic deterioration
- Major protocol violation
- Patient request
- Investigator request (reasoning required)
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9.2. withdrawal from the study

Patients may withdraw from the entire study including follow-up at any time without penalty and for any reason without prejudice to his or her future medical care. Patients may be required to withdraw from the study after discussion with the Sponsor and/or Investigator (whenever possible) for the following reasons:
- At the discretion of the Investigator.  
- At the patient's request (withdrawal of consent for the study). See Section 9.3 for withdrawal procedures.  
- Individual patient dosing noncompliance.  
- Lost to follow-up (defined as receiving no response after three attempts at contact by phone followed by one attempt by sending a certified letter).  
- If the entire study is terminated prematurely as described in Section 10.
A patient may also be withdrawn from **investigational product/study** by the Sponsor, Regulatory Authorities, or Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs).
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9.3. procedures for investigational product

When a patient is withdrawn from the study, the Investigator will notify the Sponsor promptly. In all cases, the reason(s) for premature discontinuation/withdrawal, and the primary reason must be recorded on the CRF. If a patient is prematurely withdrawn from the IP or the study for any reason, the Investigator must make every effort to perform the evaluations described for the EOT visit (performed 28 days [+14 days] after the last dose of study drug, as appropriate), and Follow-Up Visits as described in (Appendix 1 Table A1.1 and Table A1.2). If a patient discontinues due to an AE, he/she should be strongly encouraged to undergo the EOT assessment and continue to be under medical supervision until symptoms/signs cease or the condition becomes stable. If a patient withdraws consent but agrees to undergo a final examination, this will be documented on the Investigator's copy of the ICF, which will be countersigned and dated by the patient. If a patient withdraws consent due to an AE, the reason for discontinuation should be identified as 'Due to AE.' If a patient is lost to follow-up, or voluntarily withdraws from study participation, every effort should be made to determine why a patient is lost to follow-up or withdraw consent. All patients will remain on active study treatment until a cause of early treatment discontinuation occurs; these include disease progression, unacceptable toxicity, and withdrawal of consent (Section 9.1), or at Investigator discretion. Upon confirmed disease progression, or discontinuation of IP for any other reason, all further treatment for the patient's cancer will be at the Investigator's discretion, and all patients will remain in follow-up for PFS and survival, unless consent has been withdrawn.
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10. premature termination of the

The Sponsor may suspend or terminate the study or any part of the study at any time for any reason. The IP will be available to patients who continue to receive clinical benefit following the EOS as described in Section 8.4. If the Investigator suspends or terminates the study, the Investigator will promptly inform the Sponsor and the IRB/IEC and provide them with a detailed written explanation. The Investigator will also return all of the IP, IP containers, and other study materials to the Sponsor or have them destroyed according to Sponsor guidelines. Upon study completion, the Investigator will provide the Sponsor, IRB/IEC and regulatory agency with final reports and summaries as required by regulations. For investigational new drug application studies, the Investigator must submit a written report to the Sponsor and the IRB/IEC within 3 months after the completion or termination of the study.
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11. statistical methods

The statistical considerations summarized in this section outline the plan for data analysis of this study. The Statistical Analysis Plan (SAP) will provide additional detail.
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11.1. sample size justification 11.1.1.

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 v1.1 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 in the treatment arm 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. A sample size of 50 patients provide a 95% CI of (17.9%, 44.6%) when the ORR is 30%.
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11.1.2. sample size justification for

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 mutant 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 to the salivary gland and *EGFR* exon 18 mutant NSCLC cohorts may continue until up to 30 patients and the enrollment into the cervical, HR+ and CDK4/6i naïve, and TNBC cohorts may continue until up to 50 patients. A
sample size of 50 patients provide a 95% CI of (17.9%, 44.6%) when the ORRfirst is 30%. 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.
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11.2. statistical analyses

In general, efficacy and safety analyses in this study are meant to be cohort-specific and will be summarized by monotherapy and combination therapy separately. Safety analyses will also be summarized across all cohorts where appropriate.
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11.2.1. populations for analysis

For the purpose of patient disposition, the intent-to-treat (ITT) population is defined as all patients who are enrolled into the study. The primary analysis population is defined as all patients who received at least 1 dose of study treatment. This population will be used for all efficacy and safety analyses, if not otherwise specified.
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11.2.2. primary endpoint

The primary endpoint for the randomized hormone receptor positive (HR+), *HER2* negative metastatic breast cancer and metastatic cervical cancer cohorts is the confirmed objective response rate (ORR) by independent central review according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. For all other cohorts, the primary endpoint is the first objective response rate (ORRfirst) by investigator at the first post-baseline tumor assessment. The confirmed ORR and the ORRfirst will be estimated and the associated 2-sided 95% ClopperPearson confidence intervals will be determined. The ORR is defined as the proportion of patients who achieve CR or PR, per RECIST version 1.1 and confirmed by repeat tumor assessment using the same criteria performed no less than 4 weeks after the initial response. The ORRfirst is defined as the proportion of patients who achieve CR or PR, per RECIST version 1.1 or other defined response criteria, as their best overall response at the first tumor assessment.
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11.2.3. secondary endpoints

For the randomized HR+, *HER2* negative metastatic breast cancer and metastatic cervical cancer cohorts:  
- Confirmed ORR, per RECIST version 1.1, by investigator
- Duration of response (DOR), per RECIST version 1.1, by both independent central review and investigator
- Clinical benefit rate (CBR), per RECIST version 1.1, by both independent central review and investigator
- Progression-free survival (PFS), per RECIST version 1.1, by both independent central review and investigator
- For the metastatic cervical cancer cohort only, overall survival (OS)
For all other cohorts:
- Confirmed ORR, per RECIST version 1.1 or other defined response criteria, by investigator
- DOR, per RECIST version 1.1 or other defined response criteria, by investigator  
- CBR, per RECIST version 1.1 or other defined response criteria, by investigator
- PFS, per RECIST version 1.1 or other defined response criteria, by investigator
- OS
For all cohorts:
- Safety and tolerability of study treatments - Patient Reported Outcomes (PRO)
For either independent central review or investigator's assessment, the ORR is defined as the proportion of patients who achieve CR or PR as their best overall response. Complete or partial responses must be confirmed by repeat tumor assessment using same criteria performed no less than 4 weeks after the response are initially met. The confirmed ORR will be estimated and its associated 2-sided 95% Clopper-Pearson confidence intervals will be determined. The DOR is defined as the time response criteria were met until progression or death. Median DOR will be estimated via Kaplan-Meier with its associated 2-sided 95% confidence intervals. The clinical benefit rate (CBR) is defined as CR+PR +SD ≥16 weeks (≥24 weeks for the breast cancer patients). The CBR will be estimated, and its associated 2-sided 95% Clopper-Pearson confidence intervals will be determined. The PFS is defined as the interval from C1D1 until the first date on which recurrence, progression, or death due to any cause, is documented, censored at the last assessable evaluation or the last evaluation before the initiation of new anticancer therapy, if applicable. Median PFS will be estimated via Kaplan-Meier with its associated 2-sided 95% confidence intervals. Patient reported outcomes will be evaluated using the FACT-G questionnaire. The assessments will be summarized and plotted over time. Changes from baseline will be provided with both point estimates and confidence intervals.
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11.2.4. exploratory endpoints

Archival tumor tissue will be collected from all patients for centralized ERBB mutation profiling using next generation sequencing and/or other molecular techniques. Pre-, on-, and posttreatment plasma-derived cfDNA will also be collected for exploratory biomarker analysis.  
Optional biopsies (all cohorts except for all breast cancer patients and NSCLC patients where a fresh pretreatment tumor biopsy is mandatory) will be collected following disease progression and treatment discontinuation. The tissue may be subject to next-generation sequencing, gene expression profiling, immunohistochemistry and other assays to identify potential resistance mechanisms to neratinib treatment. No formal statistical analysis is planned for these exploratory objectives.
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11.2.5. adverse events serious adverse

All AEs and SAEs will be reported until 28 days after the last dose of IP(s) and will be followed until resolution or until the condition stabilizes. AEs and SAEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 16 or later and tabulated by system organ class (SOC) and preferred term. All AEs will be graded by the Investigator according to the NCI CTCAE version 4.0. All tabulations will be sorted by descending frequency of SOC and preferred term in the total column unless otherwise noted. Cause of death and the time of death (dichotomized as within 28 days of last dose versus more than 28 days after last dose) will be summarized via frequencies and percentages. Patient death listings will include all death data available including the date of death, cause of death, and any AEs resulting in death.
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11.2.6. laboratory results

Laboratory test results will be collected pretreatment (baseline) and until 28 days (+14 days) after the last dose of study treatment. Standard reference ranges will be used for missing or discrepant normal ranges. Laboratory data will be summarized in tables using descriptive statistics for baseline and each cycle/visit. Descriptive statistics will be calculated on both the actual score and the change from baseline score. Additionally, clinically significant abnormalities in laboratory results will be summarized for the post-baseline cycles/visits using frequencies and percentages. Shifts in normal/abnormal status between baseline and subsequent visits will be summarized as well.
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12. safety data collection recording

All observed or volunteered AEs regardless of treatment group or causal relationship to the IPs will be recorded on the AE page(s) of the CRF.
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12.1. definitions 12.1.1. adverse events

An AE is any untoward medical occurrence that occurs in a patient or clinical investigation patient administered a pharmaceutical product, and which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with the use of an IP, whether or not considered related to the medicinal product (definition per International Conference on Harmonisation [ICH] E2A and E6 R1).  
All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, must be recorded using medical terminology on the AE CRF page. Whenever possible, diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory infection"). All measures required for AE management must be recorded in the source document and reported according to Sponsor instructions. For all AEs, the Investigator must pursue and obtain information adequate to both determine the outcome of the AE and to assess whether it meets the criteria for classification as a SAE (see Section 12.1.3) requiring immediate notification to the Sponsor or its designated representative. For all AEs, sufficient information should be obtained by the Investigator to determine the causality of the AE. Interventions for pretreatment conditions (eg, elective cosmetic surgery) or medical procedures that were planned before study enrollment are not considered an AE. TEAEs are those events that occur or worsen on or after first dose of IP and up to 28 days after the last dose of IP.
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12.1.2. abnormal laboratory results

The criteria for determining whether an abnormal laboratory test result should be reported as an AE are as follows:
- Test result is associated with accompanying symptoms, and/or,  
- Test result requires additional diagnostic testing or medical/surgical intervention
(merely repeating an abnormal test, in the absence of any of the above conditions, does not meet criteria for reporting as an AE), and/or
- Test result leads to a change in study dosing or discontinuation from the study, significant additional concomitant drug treatment or other therapy, and/or
- Test result leads to any of the outcomes included in the definition of a SAE, and/or
- Test result is considered to be an AE by the Investigator or by the Sponsor
Any abnormal test result that is determined to be an error does not require reporting as an AE, even if it did meet one of the above criteria except for when the test result leads to any of the outcomes included in the definition of a SAE. Clinically significant laboratory results must be recorded in the patient's CRF.
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12.1.3. serious adverse events

An SAE is defined as any untoward medical occurrence that at any dose (ICH E2A and E6 R1):  
- Results in death.  
- Is life-threatening.  
This means that the patient is at risk of death at the time of the event; it does not mean that the event hypothetically might have caused death if it were more severe.  
- Requires inpatient hospitalization or prolongation of existing hospitalization.  
- Results in persistent or significant disability or incapacity.  
- Is a congenital anomaly or birth defect.
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical event(s) that may not be immediately life-threatening or result in death or hospitalization but that may jeopardize the patient or require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse. Disease progression should not be recorded as an AE or SAE term; instead, signs and symptoms of clinical sequelae resulting from disease progression will be reported if they fulfill the SAE definition.
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12.1.4. hospitalization

Any inpatient hospital admission that includes a minimum of an overnight stay to a healthcare facility meets the criteria for 'hospitalization.' Admission also includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric wing to a medical floor, medical floor to a coronary care unit, neurological floor to a tuberculosis unit). The following are not considered to be hospitalization:  
- Rehabilitation facilities
- Hospice facilities
- Respite care (eg, caregiver relief)
- Skilled nursing facilities
- Nursing homes - Routine emergency room admissions
- Same day surgeries (as outpatient /same day/ambulatory procedures)
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is not in itself a SAE. Examples include:  
- Admission for treatment of a preexisting condition not associated with the development of a new AE or with a worsening of the preexisting condition (eg, for work-up of persistent pretreatment lab abnormality).  
- Social admission (eg, patient has no place to sleep).  
- Administrative admission (eg, for yearly physical examination). - Protocol-specified admission during a study (eg, for a procedure required by the study protocol).  
- Optional admission not associated with a precipitating clinical AE (eg, for elective cosmetic surgery).  
- Hospitalization for observation without a medical AE. - Pre-planned treatments or surgical procedures should be noted in the baseline documentation for the individual patient.  
- Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be reported as AEs. However, the medical condition for which the procedure was performed should be reported if it meets the definition of an AE. For example, an acute appendicitis that begins during the AE reporting period should be reported as the AE, and the resulting appendectomy should be recorded as treatment of the AE.
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12.1.5. suspected unexpected serious adverse

Suspected Unexpected Serious Adverse Reactions (SUSARs) are events which are serious as per the above criteria (see Section 12.1.3 Serious Adverse Events), the nature or severity of which is not consistent with the applicable product information (Neratinib IB) and are judged by the Investigator or by the Sponsor to be related to the IP.
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12.1.6. severity assessment

AEs will be graded by the Investigator according to the NCI CTCAE version 4.0 (Publication Date: 14-Jun-2010, https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-0614_QuickReference_8.5x11.pdf), according to the following general categories:  
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.  
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting ageappropriate instrumental activities of daily living.  
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living.
Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE.  
Note the distinction between the severity and the seriousness of an AE: A severe event is not necessarily a serious event. For example, a headache may be severe (interferes significantly with patient's usual function) but would not be classified as serious unless it meets one of the criteria for SAEs, listed above.
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12.1.7. causality assessment

The Investigator's assessment of causality must be provided for all AEs (serious and non-serious); the Investigator must record the causal relationship in the CRF and report such an assessment in accordance with the serious adverse reporting requirements, if applicable. A
suspected adverse reaction means any AE for which there is a reasonable possibility that the IP caused the AE. An Investigator's causality assessment is the determination of whether there exists a reasonable possibility that the IP caused or contributed to an AE; generally, the facts (evidence) or arguments to suggest a causal relationship should be provided. If the Investigator does not know whether or not the IP caused the event, then the event will be handled as "related to investigational product" for reporting purposes, as defined by the Sponsor (see Section 12.2 and Section 12.3). If the Investigator's causality assessment is "unknown but not related to investigational product," this should be clearly documented on study records. For all AEs, sufficient information should be obtained by the Investigator to determine the causality of the AE (eg, IP or other illness). The relationship of the AE to the study treatment (IP or other concomitant medications) will be assessed following the definitions below:  
- 'No' (unrelated): Any event that does not follow a reasonable temporal sequence from administration of the IP AND is likely to have been produced by the patient's clinical state or other modes of therapy administered to the patient.  
- 'Yes' (related): Any reaction that follows a reasonable temporal sequence from administration of the IP AND follows a known response pattern to the suspected IP
AND recurs with re-challenge, AND/OR is improved by stopping the IP or reducing the dose.
In addition, if the Investigator determines an AE is associated with study procedures, the Investigator must record this causal relationship on the AE CRF page and report such an assessment in accordance with the SAE reporting requirements, if applicable.
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12.1.8. special reporting situations

Safety events of interest due to the Sponsor's IP that may require expedited reporting and/or safety evaluation include, but are not limited to:
- Overdose of the IP.  
- Suspected abuse/misuse of the IP. - Inadvertent or accidental exposure to the IP.  
- Medication error that may result from the administration or consumption of the wrong drug, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
- Suspected transmission via the IP of an infectious agent.
Special reporting situations should be recorded on the AE CRF page. Any special reporting situation that meets the criteria of a SAE should be recorded on the SAE form and related as required (see Section 12.3).
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12.2. reporting adverse events

For serious and non-serious AEs, the reporting period to the Sponsor (or its designated representative) begins from the time that the patient signs the informed consent, which is obtained prior to the patient's participation in the study, ie, prior to undergoing any study-related procedure and/or receiving IP, through 28 calendar days after the last administration of the IP. For all AEs with causal relationship to the IP, follow-up by the Investigator may be required until the event or its sequelae resolve or stabilize at the level acceptable to the Investigator, and the Sponsor concurs with that assessment. If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs ends at the time the new treatment is started. Death must be reported if it occurs during the SAE reporting period after the last dose of the IP, irrespective of any intervening treatment. The Sponsor will evaluate any safety information that is spontaneously reported by an Investigator beyond the time frame specified in the protocol.
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12.3. reporting serious adverse events

All SAEs, irrespective of relationship to the IP, must be reported within 24 hours of discovery or notification of the event to the Sponsor or designated representative using the SAE form. The SAE form must be signed by the Investigator. In particular, if the SAE is fatal or life-threatening, notification to the Sponsor must be made immediately, irrespective of the extent of available AE information. This timeframe also applies to follow-up information on previously forwarded SAE reports as well as to the initial and follow-up reporting of exposure during pregnancy and exposure via breast feeding cases. For SAE reporting information, please refer to the Study Contact List which is provided as a separate document. Relevant medical records should be provided to the Sponsor or its designated representative as soon as they become available; autopsy reports should be provided for deaths if available. Should an Investigator be made aware of any SAEs occurring any time after the reporting period that may be causally related to the administration of neratinib, it should be promptly reported. All SAEs that have not resolved by the end of the study, or that have not resolved upon discontinuation of the patient's participation in the study, must be followed until any of the following occurs:  
- The event resolves. - The event stabilizes.  
- The event returns to baseline, if a baseline value/status is available.  
- The event can be attributed to agents other than the IP or to factors unrelated to study conduct.  
- It becomes unlikely that any additional information can be obtained (patient or health care practitioner refusal to provide additional information, lost to follow-up after demonstration of due diligence with follow-up efforts).
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12.4. pregnancy

All initial reports of pregnancy must be reported to the Sponsor by the investigational staff within 24 hours of their knowledge of the event using the appropriate Exposure-In-Utero (EIU) form. For IPs in neratinib studies, an exposure during pregnancy occurs if:  
- A female becomes, or is found to be, pregnant either while receiving or having been directly exposed (eg, environmental exposure) to the IP, or the female becomes or is found to be pregnant after discontinuing and/or being directly exposed to the IP (maternal exposure) within 28 days after last dose of or exposure to study drug. See Section 9.1 for action to be taken with IP.  
- A male partner of a pregnant female has been exposed to the IP, either due to treatment or environmental exposure, within 3 months prior to the time of conception and/or is exposed during his partner's pregnancy (paternal exposure).
If any study patient or study patient's partner becomes or is found to be pregnant during the study patient's treatment with the IP or exposure as defined above, the Investigator must submit this information on an EIU form to the Sponsor (or its designated representative) promptly. In addition, the Investigator must submit information regarding environmental exposure to an IP in a pregnant woman (eg, a patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or spillage) using the EIU form. This must be done irrespective of whether an AE has occurred and within 24 hours of awareness of the pregnancy. The information submitted should include the anticipated date of delivery (see following information related to an induced termination of pregnancy). Follow-up is conducted to obtain pregnancy outcome information on all exposure during pregnancy reports with an unknown outcome. The Investigator will follow the pregnancy until completion or until pregnancy termination (eg, induced abortion) and then notify the Sponsor or its designated representative of the outcome as a follow-up to the initial EIU form. In the case of a live birth, the structural integrity of the neonate can be assessed at the time of birth. In the event of a termination, the reason(s) for termination should be specified and, if clinically possible, the structural integrity of the terminated fetus should be assessed by gross visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly and the findings are reported). If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (eg, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [including that in a live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the Investigator should follow the procedures for reporting SAEs. Additional information about pregnancy outcomes that are classified as SAEs follows:
- "Spontaneous abortion" includes miscarriage and missed abortion.  
- All neonatal deaths that occur within 1 month of birth should be reported, without regard to causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs when the Investigator assesses the neonatal death as related to exposure to IP.
Additional information regarding the exposure during pregnancy may be requested by the Investigator. Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be required.
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12.5. sponsor reporting requirements to

The Sponsor assumes responsibility for reporting of AEs including SUSARs according to local and international regulations, as appropriate. The Investigator (or the Sponsor where required) must report these events to the appropriate IEC/IRB that approved the protocol unless otherwise required and documented by the IEC/IRB.
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13. ethical legal and administrative

The Sponsor of this study may delegate some administrative aspects of this study to a duly authorized representative including, but not limited to, study initiation, monitoring, and management of SAE reports.
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13.1. data collection processing and

All data captured for the study is planned to be electronic. However, if necessary, data captured may be performed using paper Case Report Forms (CRFs). The Investigator agrees to enter into the electronic data capture (EDC) system all data associated with a patient's study-related visit within 5 working days of that visit. CRFs will be provided by the Sponsor or its representative and should be handled in accordance with the instructions provided by the Sponsor or designated representative. The Investigator is responsible for maintaining adequate and accurate CRFs which have been designed to record all observations and other data pertinent to the clinical investigation. Each CRF should be filled out completely by the Investigator or delegate as stated in the Site Delegation List. If paper CRFs are used, then all CRFs should be completed in a neat legible manner to ensure accurate interpretation of the data; a black ball-point pen should be used to ensure the clarity of reproduced copies of all CRFs. Incorrect entries should be crossed with a single line. Corrections must be made adjacent to the item to be altered, initialed and dated with the reason for the correction if necessary, by an authorized (Investigator/study team designee) person. Overwriting of this information or use of liquid correcting fluid is not allowed. The data should be reviewed, signed and dated by the Investigator for accuracy and completeness. Once the site monitor has verified the contents of the completed CRF pages against the source data, queries may be raised if the data are unclear or contradictory. These queries must be addressed by the Investigator and verified by the clinical research associate within 5 days of receipt. After all the data issues are resolved, these CRFs may be locked to prevent any further data changes.
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13.1.2. study monitoring and access

To ensure compliance with relevant regulations, data generated by this study must be available for inspection upon request by representatives of the US FDA, the European Medicines Agency (EMA), other national authorities, eg, the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA), the German Federal Institute for Drugs and Medical Devices (BfArM), and local health authorities, the Sponsor and representatives, and the IRB/EC for each study site. The Investigator will permit authorized representatives of the Sponsor, the respective national or local health authorities, and auditors to inspect facilities and records relevant to this study. The Sponsor or representative's monitor is responsible for verifying the CRFs at regular intervals throughout the study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; and adherence to local regulations on the conduct of clinical research. Source data to be reviewed during this study will include, but is not restricted to patient's medical file, patient's diary (if applicable), and original laboratory test, histology, and pathology reports. All key data must be recorded in the patient's hospital notes.  
Auditors, IEC/IRB and/or regulatory inspectors will also have access to the CRFs and source documents. The ICF will include a statement by which the patient allows the monitor/auditor/inspector from the IEC/IRB or regulatory authority access to source data (eg, patient's medical file, appointment books, original laboratory test reports, X-rays, etc.) that substantiate information in the CRFs. These personnel, bound by professional secrecy, will not disclose any personal information or personal drug information.
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13.1.3. data quality assurance

In accordance with ICH E6 Good Clinical Practice (GCP) and the Sponsor's audit plans, this study may be selected for audit by representatives from the Sponsor's (or designee's) Quality Assurance Department. Inspection of site facilities (eg, pharmacy, drug storage areas, laboratories) and review of study-related records will occur to evaluate the study conduct and compliance with the protocol, ICH GCP (ICH E6), US Investigational Drugs (21CFR50, 54, 56, and 312), European Union (EU) Clinical Studies Directive (Directive 2001/20/EC), and applicable regional regulatory requirements. The Sponsor's representatives are responsible for contacting and visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting the various records of the clinical study (eg, CRFs and other pertinent data) provided that patient confidentiality is respected. The Investigator agrees to cooperate with the Sponsor representative to ensure that any problems detected in the course of these inspection visits, including delays in completing CRFs, are resolved.
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13.1.4. data processing

All data will be entered by site personnel into the electronic data capture system/CRF (as detailed in Section 13.1.1).  
The data-review and data-handling document will include specifications for consistency and plausibility checks on data and will also include data-handling rules for obvious data errors. Query/correction sheets for unresolved queries will be sent to the study monitors for resolution with the Investigator. The database will be updated on the basis of signed corrections. Previous and concomitant medications will be coded using the World Health Organization Drug Reference List (WHO Drug), which employs the Anatomical Therapeutic Chemical (ATC) classification system. Medical history and AEs will be coded using the MedDRA terminology. The versions of the coding dictionaries will be provided in the Clinical Study Report.
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13.1.5. retention of data and

As described in the ICH GCP Guidelines, 'essential documents', including CRFs, source documents, ICFs, laboratory test results, and drug inventory records, should be retained by the Investigator until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the IP. These documents should be retained for a longer period, however, if required by the applicable regulatory requirements or by an agreement with the Sponsor. The Investigator should obtain written permission from the Sponsor prior to the destruction of any study document.  
These records should be made available at reasonable times for inspection and duplication, if required, by a properly authorized representative of the US FDA in accordance with 21 CFR 312.68 or other National Regulatory Authorities.
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13.2. ethical aspects 13.2.1. good

This protocol accords with the principles of the Declaration of Helsinki as set forth at the 18th World Medicines Association (Declaration of Helsinki, 1964) and amendments thereto. The most current amended version will be in effect. The procedures set out in this study protocol are also designed to ensure that the Sponsor and Investigator abide by the principles of the GCP guidelines of the ICH and in keeping with local legal requirements.
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13.2.2. informed consent responsibilities

It is the responsibility of the Investigator to obtain written informed consent from the patient or patient's legal representative. If informed consent has not been obtained, no protocol-required procedures are to be performed on the patient and no patient data are to be transferred to the Sponsor. Documentation of informed consent must be recorded in the source documents for each patient. The study will be discussed with the patient, and the patient will receive written information and an explanation of what the study involves, ie, the objectives, potential benefits and risk, inconveniences, and the patient's rights and responsibilities. If applicable, the information will be provided in a certified translation of the local language. A signed, IRB/IEC approved ICF must be obtained from the patient before any study specific procedures can occur. Confirmation of the patient's informed consent and the informed consent process must also be documented in the patient's medical record. Signed ICFs must remain in each patient's study file and must be available for verification by study monitors at any time. A copy of the fully signed ICFs will be given to the patient. If the IEC/IRB requires modification of this form, the documentation supporting this requirement must be provided to the Sponsor, along with the new version. The Sponsor reserves the right to reject these modifications, should they not cover the minimum information required by ICH GCP. A patient wishing to participate must also provide Authorization for Use and Release of Health and Research Study Information (US only) or Data Protection Consent (Europe only) prior to any study-related procedures or change in treatment. If a patient is not physically or mentally competent to understand and to give their informed consent to participate in the study (eg, is blind or illiterate), a legally acceptable representative or impartial witness as applicable, may sign the ICF on behalf of the patient. It remains the responsibility of the principal Investigator to assure that the patient is suitable for inclusion in this study and will be able to adhere to all study procedures throughout the course of the study.  
The explicit wish of a minor or mentally incapacitated adult, who is capable of forming an opinion and assessing the study information, to refuse participation in or to be withdrawn from the study at any time will be respected by the Investigator. If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the protocol. If the consent form is revised, it must be reviewed and approved by the appropriate IEC/IRB and signed by all patients subsequently enrolled in the study as well as those currently enrolled in the study.
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13.3. other study administration aspects

The protocol (approved by the Sponsor or its representative) will be submitted to the IRB/IEC for review and it must be approved before the study is initiated. Prior to implementing changes in the study, the Sponsor will produce a protocol amendment and the IRB/IEC must also approve any amendments to the protocol. Any change in the study plan requires a protocol amendment. An Investigator must not make any changes to the study without IRB/IEC and Sponsor approval except when necessary to eliminate apparent immediate hazards to the patients. A protocol change intended to eliminate an apparent immediate hazard to patients may be implemented immediately, but the change must then be documented in an amendment, reported to the IRB/IEC within 5 working days, and submitted to the appropriate regulatory agency in the required time frame. All protocol amendments must be reviewed and approved by the Sponsor and the Investigator.
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13.3.2. investigator responsibilities

The Investigator undertakes to perform the study in compliance with the protocol, ICH Guidelines per GCP and the applicable regulatory requirements. A copy of the guidelines will be available in the Investigator Site File. It is the Investigator's responsibility to ensure that adequate time and appropriate resources are available at the investigational site prior to commitment to participate in this study. The Investigator should also be able to demonstrate a potential for recruiting the required number of suitable patients within the agreed recruitment period. The Investigator will maintain a list of appropriately qualified persons to whom the Investigator has delegated significant study-related tasks. An up-to-date copy of the curriculum vitae for the Investigator and sub-Investigator(s) will be provided to the Sponsor (or its representative) before starting the study. If the patient has a primary physician, the Investigator should, with the patient's consent, inform the primary physician of the patient's participation in the study. Agreement with the final clinical study report will be documented by the signed and dated signature of the principal or coordinating Investigator in compliance with ICH E3. The Investigator must adhere to the protocol as detailed in this document. The Investigator will be responsible for enrolling only those patients who have met protocol eligibility criteria. The Investigators will be required to sign an Investigator agreement to confirm acceptance and willingness to comply with the study protocol.  
It is the Investigator's responsibility to communicate with their local IRB/IEC to ensure accurate and timely information is provided at all stages during the study. In particular, the appropriate approvals must be in place prior to recruitment, notification of any SAEs during the study must take place and the IRB/IEC must be informed of study completion. It is the responsibility of the Investigator to submit this protocol, the final approved informed consent document (approved by the Sponsor or its representative), relevant supporting information, all types of patient recruitment or advertisement information (approved by the Sponsor or its representative), and all written materials provided to the study patients to the IRB/IEC for review; these must be approved before the study is initiated or use. Prior to implementing changes in the study, the Sponsor will produce a protocol amendment and the IRB/IEC must also approve any amendments to the protocol. On the approval letter, the study (title, protocol number and version), the documents reviewed (protocol, informed consent material, amendments) and the date of review should be clearly stated. Investigational product supplies will not be released, and the patient recruitment will not begin until this written approval has been received by the Sponsor or its designee. The Investigator is responsible for keeping the IRB/IEC appraised of the progress of the study and of any changes made to the protocol as deemed appropriate, and at least once per year. The Investigator must also keep the IRB/IEC informed of any serious and significant AEs.
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13.3.3. patient confidentiality

Data collected during this study may be used to support the development, registration or marketing of neratinib. All data collected during the study will be controlled by the Sponsor (or designee) and the Sponsor will abide by all relevant data protection laws. After a patient has consented to take part in the study, their medical records and the data collected during the study will be reviewed by representatives of the Sponsor and/or the company organizing the research on the Sponsor's behalf to confirm that the data collected are accurate and for the purpose of analyzing the results. These records and data may additionally be reviewed by auditors or by regulatory authorities. The patient's name, however, will not be disclosed outside the hospital. They will be known by a unique patient number. The results of this study may be used in other countries throughout the world that have ensured an adequate level of protection for personal data. Written Authorization (US sites only) or Data Protection Consent (European sites only) is to be obtained from each patient prior to enrollment into the study, and/or from the patient 's legally authorized representative in accordance with the applicable privacy requirements [eg, the Health Insurance Portability and Accountability Act of 1996 Standards for Privacy of Individually Identifiable Health Information ("HIPAA"), European Union Data Protection Directive 95/46/EC ("EU Directive") and any other state and country privacy requirements]. If the patient is under the legal age of consent, the Authorization (US sites only) or Data Protection form (European sites only) must be signed by the legally authorized representative in accordance with the applicable privacy requirements and other state and country privacy requirements.
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13.3.4. financial disclosure

The Investigator will be required to disclose any financial arrangement whereby the value of the compensation for conducting the study could be influenced by the outcome of the study; any significant payments of other sorts from the Sponsor, such as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation, or honoraria; any proprietary interest in neratinib; any significant equity interest in the Sponsor, as defined in the US Code of Federal Regulations (21 CFR 54 2(b)). In consideration of participation in the study, the Sponsor will pay the Investigator, study site or nominated payee the sums set out in the payment schedule attached to the Investigator Agreement.
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13.3.5. publication policy

The Sponsor encourages publication of results derived from the clinical research it sponsors. Publications include a paper in a peer reviewed medical journal, abstract submission with a poster or oral presentation at a scientific meeting or making results public by some other means. The Sponsor will retain the right to review all material prior to presentation or submission for publication and neither institution(s) nor Study Co-chairs/Principal Investigator(s) are permitted to publish/present the results of the study, in part or in their entirety, without the written authorization of the Sponsor. The review is aimed at protecting the Sponsor's pre-existing proprietary information and commercial interests. In all publications, the study is to be identified as PUMA-NER-5201. The Study Principal Investigator(s) shall be free to publish or present, subject to the timing described in the Clinical Study Agreement.
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14. reference list

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Swisher SG, Erasmus J, Maish M, et al. 2-Fluoro-2-deoxy-D-glucose positron emission tomography imaging is predictive of pathologic response and survival after preoperative chemoradiation in patients with esophageal carcinoma. *Cancer* 2004; 101:1776-1785.  
Tatro DS. Drug Interaction Facts: The Authority on Drug Interactions. Wolters Kluwer Health, 2012. Ustaris F, Saura C, Di Palma J, et al. Effective management and prevention of neratinib-induced diarrhea. *Am J Hematol Oncol* 2015; 11(11):13–22. Van den Abbeele AD. The lessons of GIST--PET and PET/CT: a new paradigm for imaging. Oncologist 2008; 13 (Suppl 2):8-13. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving Considerations for PET Response Criteria in Solid Tumors. *J Nucl Med* 2009; 50:122S-150S.  
Weber WA, Wieder H. Monitoring chemotherapy and radiotherapy of solid tumors. Eur J Nucl Med Mol Imaging 2006; 33 (Suppl 1):27-37.  
Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nature Reviews Molecular Cell Biology 2001; 2(2): 127-137. Yatabe Y, Kerr KM, Utomo A, et al. EGFR mutation testing practices within the Asia Pacific region: results of a multicenter diagnostic survey. *J Thorac Oncol* 2015;10:438-445. Young H, Baum R, Ceremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]-fuorodeoxyglucose and positron emission tomography: Review and 1999 EORTC recommendations*. Eur J Cancer* 1999;35:1773-1782. Zaczek A, Brandt B, Bielawski KP. The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches. *Histology and* Histopathology 2005; 20(3): 1005-1015. 15. SIGNATURE PAGES Declaration of Sponsor or Responsible Medical Officer Title: An Open-Label, Phase 2 Basket Study of Neratinib in Patients With Solid Tumors With Somatic Activating HER Mutations
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study number puma-ner-5201

I have read and approve this protocol. My signature, in conjunction with the signature of the Investigator, confirms the agreement of both parties that the clinical study will be conducted in accordance with the protocol and all applicable laws, regulations, and guidelines, including, but not limited to, the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), the United States Code of Federal Regulations (CFR), the Directives of the European Union, the ethical principles that have their origins in the Declaration of Helsinki, and applicable privacy laws.  
__ ___________________ _____________________  
  Title  
  
Declaration of Principal Investigator Title: An Open-Label, Phase 2 Basket Study of Neratinib in Patients With Solid Tumors With Somatic Activating HER Mutations  
I have read and approve this protocol. My signature, in conjunction with the signature of the Sponsor, confirms the agreement of both parties that the clinical study will be conducted in accordance with the protocol and all applicable laws, regulations, and guidelines, including, but not limited to, the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), the United States Code of Federal Regulations (CFR), the Directives of the European Union, the ethical principles that have their origins in the Declaration of Helsinki, and applicable privacy laws.  
The study will not be commenced without the prior written approval of a properly constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). No changes will be made to the study protocol without the prior written approval of the Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to the patients. Nothing in this document is intended to limit the authority of a physician to provide emergency medical care under applicable regulations. _____________________________________ Signature  
_____________________________________ ______________________________ Name Date _____________________________________ ______________________________ Title Institution (block letters) _____________________________________ ______________________________ Address Phone number  
16. APPENDICES
APPENDIX 1 SCHEDULE OF PROCEDURES  
| Table A1.1.                                                                            | Schedule of Study Procedures for Cohorts Receiving Trastuzumab Combination Therapy Event Screening Treatment   | Follow-upb                                                  |         |         |         |      |    |     |    |     |     |     |     |     |    |
|----------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|---------|---------|---------|------|----|-----|----|-----|-----|-----|-----|-----|----|
| Visit                                                                                  | Cycle 1                                                                                                        | Cycle 2                                                     | Cycle 3 | Cycle 4 | Cycle 5 | EOTa |    |     |    |     |     |     |     |     |    |
| Study Week                                                                             | W1                                                                                                             | W2                                                          | W3      | W4      | W5      | W6   | W7 | W8  | W9 | W10 | W11 | W12 | W13 |     |    |
| Within 28                                                                              | Within 14                                                                                                      |                                                             |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Cycle Day                                                                              | days of C1D1                                                                                                   | days of C1D1                                                | D1      | D8      | D15     | D1   | D8 | D15 | D1 | D8  | D15 | D1  | D8  | D15 | D1 |
| Informed consent                                                                       | X                                                                                                              |                                                             |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Demographics                                                                           | X                                                                                                              |                                                             |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Medical, cancer, and medication historyc                                               | X                                                                                                              |                                                             |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Physical examinationd /vital signsd                                                    | X                                                                                                              | Xe                                                          | X       | X       | X       | X    | X  |     |    |     |     |     |     |     |    |
| Electrocardiogram                                                                      | X                                                                                                              | X                                                           |         |         |         |      |    |     |    |     |     |     |     |     |    |
| ECHO/MUGAf                                                                             | X                                                                                                              | Xf                                                          | X       |         |         |      |    |     |    |     |     |     |     |     |    |
| Urine testg / Pregnancy testg                                                          | X                                                                                                              |                                                             |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Hematologyh / Serum chemistry panelh                                                   | X                                                                                                              | Xi                                                          | X       | X       | X       | X    | X  |     |    |     |     |     |     |     |    |
| Xj                                                                                     | Xj                                                                                                             | Xj                                                          |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Plasma collection for cfDNA biomarker  analysisj  Whole blood sample for germline DNAk | X                                                                                                              |                                                             |         |         |         |      |    |     |    |     |     |     |     |     |    |
| ECOG status                                                                            | X                                                                                                              | Xe                                                          | X       | X       | X       | X    |    |     |    |     |     |     |     |     |    |
| Neratinibl                                                                             | X                                                                                                              |                                                             |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Trastuzumabl                                                                           | X                                                                                                              | X                                                           | X       | X       | X       |      |    |     |    |     |     |     |     |     |    |
| Fulvestrantl                                                                           | X                                                                                                              | X                                                           | X       | X       | X       |      |    |     |    |     |     |     |     |     |    |
| Tumor evaluationm                                                                      | Xm                                                                                                             | Xm                                                          | Xm      | Xm      |         |      |    |     |    |     |     |     |     |     |    |
| MD/RN Phone calln                                                                      | Xn                                                                                                             | Xo                                                          |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Mandatory fresh pretreatment tumor                                                     | X                                                                                                              |                                                             |         |         |         |      |    |     |    |     |     |     |     |     |    |
| biopsy for all breast cancer patients                                                  | Xp                                                                                                             |                                                             |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Archival and/or fresh pretreatment  metastatic tumor tissue sample for all  patients Optional on-treatment or end-oftreatment fresh core tumor biopsyq                                                                                        | Xq                                                                                                             | Xq                                                          |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Loperamide antidiarrheal treatmentr                                                    | Administered orally daily                                                                                      | Administered orally as needed (not to exceed 16 mg per day) |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Patient Diarys                                                                         | X                                                                                                              |                                                             |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Concomitant therapy                                                                    | Collected continuously throughout study period                                                                 |                                                             |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Adverse eventst                                                                        | Collected continuously throughout study period                                                                 |                                                             |         |         |         |      |    |     |    |     |     |     |     |     |    |
| Patient Reported Outcomesu                                                             | Xu                                                                                                             | Xu                                                          | Xu      | Xu      | Xu      | Xu   | Xu |     |    |     |     |     |     |     |    |  
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; C1D1 = Cycle 1 Day 1; cfDNA = cell-fee DNA; CT = computerized tomography; D = Day; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FFPE = formalin-fixed paraffin embedded; Hb = hemoglobin; Hct = hematocrit; ICF = informed consent form; IP = Investigational Product; LDH = lactate dehydrogenase; MD = medical doctor; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition scan; PD = progressive disease; PET = positron emission tomography; RECIST = Response Evaluation Criteria in Solid Tumors; RBC = red blood cells; RN = registered nurse; W = week; WBC = white blood cell a. EOT follow-up assessments will be conducted 28 days (+14 days) after the last administration of IP(s). AEs must be followed for 28 days after the last administration of IP(s). b. Follow-up visits will occur every 3 cycles (9 weeks ±7 days) for patients discontinuing treatment for any reason other than disease progression until objective disease progression is reported per RECIST v 1.1 (or other response criteria). After disease progression, all patients will be followed every 12 weeks for survival and anti-cancer medication taken will be recorded.  
c. Collect chronic medical condition and medical history of significance (including smoking history only for lung cancer patients), or symptoms experienced during the previous 30 days and those ongoing at the time of screening, and any medical conditions that require medication. Identify start of current medical conditions by at least providing the year of onset.  
d. Physical examination may be delegated and performed by a properly trained nurse practitioner, physician's assistant, or equivalent. Full physical examination at screening, C1D1, and thereafter should be a detailed/brief (system-guided) physical examination to evaluate any clinically significant abnormalities; including worsening of medical history conditions. Vital signs include pulse, blood pressure, temperature
(in Celsius) and respiration rate taken before dosing. Also includes height (screening only) and weight.  
e. Physical examination / ECOG status does not need to be repeated if performed within 72 hours prior to C1D1. f. Patients treated with neratinib in combination with trastuzumab will have ECHO/MUGAs performed at baseline, at the beginning of Week 13, every 4 cycles (12 weeks ± 7 days) thereafter, at EOT, and every 6 months up to 24 months after the last dose of trastuzumb.  
g. Laboratory urinalysis or by urine dipstick (blood, protein, glucose, and microscopic examination, if abnormal). Urine or serum pregnancy test only for women of child-bearing potential (at screening, and to be repeated only if performed outside 72 hours of C1D1).  
h. Hematology panel: Hct, Hb, platelet count, RBC count, and WBC count with differential. Serum chemistry: albumin, alkaline phosphatase, ALT, AST, BUN, calcium, chloride, serum creatinine, glucose (nonfasting), LDH, magnesium, phosphorous, potassium, serum cholesterol (non-fasting), total bilirubin, total protein, and sodium. Following C1, laboratory tests may take place ± 2 days before Day 1.  
i. Laboratory assessments are not required on C1D1 if previously obtained within 72 hours prior to C1D1 as part of screening, with no clinically significant findings.  
j. Plasma collection for cfDNA biomarker analysis at screening (if collected on C1D1, it has to be done prior to the first IP dose), at the beginning of Week 10 (ORRfirst), and every 3 cycles (9 weeks ± 7 days)
thereafter, and during the EOT visit.  
k. Whole blood sample for research (single collection) obtained during study, preferably during screening or within the first cycle of therapy. l. Neratinib, trastuzumab, and fulvestrant administration performed as described in Section 5.1. Following C1, fulvestrant administration may take place ± 2 days. m. Tumor assessment at screening should occur within 4 weeks of C1D1, as appropriate. Post-treatment disease assessment by CT or PET/CT scan or MRI of the chest, abdomen and pelvis, as appropriate, will be conducted at the beginning of Week 10 (ORRfirst), every 3 cycles (9 weeks ± 7 days) thereafter until 1 year and annually (once per year). Following one year on therapy, scans may move to every 4 cycles for trastuzumab-containing regimens. Following two years on therapy, scans may move to every 5 cycles for trastuzumab-containing regimens. The scans must be obtained and reviewed prior to start of the next cycle. CT or PET/CT or MRI should be done only at EOT if not done within the previous 4 weeks, or if required to confirm an objective response. Overall response will be scored by independent assessment and by the Investigator per RECIST v1.1 using the algorithms defined in the protocol. Tumor assessments should be continued every 3 cycles (9 weeks ± 7 days) for any patients ending therapy for any reason other than radiological PD. Patients with a history of brain metastases or those symptomatic for brain metastases will have a brain CT or MRI at baseline. For patients who enrolled prior to Amendment 6, the same method of measurement (eg PET/CT) and same method of disease assessment (eg metabolic response by PET Response Criteria) should continue through final assessments.  
n. Phone call to patient 1 day, 2 days, and 3 days after the first dose of neratinib (C1D1) to check on diarrhea symptoms and patient compliance with anti-diarrheal therapy.  
o. AEs, SAEs, and clinically significant abnormal laboratory results should be followed for 28 days after the last dose of IP(s); this information may be collected at the EOT visit or via phone call. Follow patients via phone call every 12 weeks (±14 days) after disease progression to monitor survival.  
p. Archival tissue sample obtained during screening or within the first cycle of therapy. In cases where a patient is enrolled based on a documented HER mutation derived from a cfDNA specimen (ie, liquid biopsy),
a mandatory archival FFPE or fresh-tumor biopsy should be submitted for retrospective central confirmation of the mutation.  
q. Optional fresh core tumor biopsy from all patients upon progression of disease.  
r. Loperamide antidiarrheal treatment should be dispensed with the initial supply of neratinib. 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.  
s. Patient Diary will be provided by the Investigator for the patient to record daily study medication intake for every cycle, and frequency and management of diarrhea in the first 2 cycles.  
| Neratinib Tablets (PB-272)   | 03-FEB-2021   |
|------------------------------|---------------|
| PUMA-NER-5201                | AMENDMENT 7   |  
t. Symptoms should be assessed from signing of ICF and during any protocol visit that includes a physical examination. AEs should be followed for 28 days after last administration of IP(s).  
u. FACT-G will be performed at Screening, C1D1 and at the beginning of each cycle for up to 6 months or EOT, whichever comes first.  
Table A1.2. Schedule of Study Procedures for Cohorts Not Receiving Trastuzumab  
| Event                                                                                                                                                                                                                                                                                                                                                                                     | Screening                                      | Treatment                                                    | Follow-upb   |         |      |     |    |    |     |     |     |     |     |     |    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------|--------------------------------------------------------------|--------------|---------|------|-----|----|----|-----|-----|-----|-----|-----|-----|----|
| Visit                                                                                                                                                                                                                                                                                                                                                                                     | Cycle 1                                        | Cycle 2                                                      | Cycle 3      | Cycle 4 | EOTa |     |    |    |     |     |     |     |     |     |    |
| Study Week                                                                                                                                                                                                                                                                                                                                                                                | W1                                             | W2                                                           | W3           | W4      | W5   | W6  | W7 | W8 | W9  | W10 | W11 | W12 | W13 |     |    |
| Within 28                                                                                                                                                                                                                                                                                                                                                                                 | Within 14                                      |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Cycle Day                                                                                                                                                                                                                                                                                                                                                                                 | days of C1D1                                   | days of C1D1                                                 | D1           | D8      | D15  | D22 | D1 | D8 | D15 | D22 | D1  | D8  | D15 | D22 | D1 |
| Informed consent                                                                                                                                                                                                                                                                                                                                                                          | X                                              |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Demographics                                                                                                                                                                                                                                                                                                                                                                              | X                                              |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Medical, cancer, and medication historyc                                                                                                                                                                                                                                                                                                                                                  | X                                              |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Physical examinationd /vital signsd                                                                                                                                                                                                                                                                                                                                                       | X                                              | Xe                                                           | X            | X       | X    | X   |    |    |     |     |     |     |     |     |    |
| Electrocardiogramf                                                                                                                                                                                                                                                                                                                                                                        | X                                              | Xf                                                           | X            |         |      |     |    |    |     |     |     |     |     |     |    |
| ECHO/MUGA                                                                                                                                                                                                                                                                                                                                                                                 | X                                              | X                                                            |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Urine testg / Pregnancy testg                                                                                                                                                                                                                                                                                                                                                             | X                                              |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Hematologyh / Serum chemistry panelh                                                                                                                                                                                                                                                                                                                                                      | X                                              | Xi                                                           | X            | X       | X    | X   |    |    |     |     |     |     |     |     |    |
| Plasma collection for cfDNA biomarker                                                                                                                                                                                                                                                                                                                                                     | Xj                                             | Xj                                                           | Xj           |         |      |     |    |    |     |     |     |     |     |     |    |
| analysisj Whole blood sample for germline DNAk                                                                                                                                                                                                                                                                                                                                            | X                                              |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |
| ECOG status                                                                                                                                                                                                                                                                                                                                                                               | X                                              | Xe                                                           | X            | X       | X    |     |    |    |     |     |     |     |     |     |    |
| Neratinibl                                                                                                                                                                                                                                                                                                                                                                                | X                                              |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Fulvestrantl                                                                                                                                                                                                                                                                                                                                                                              | X                                              | X                                                            | X            | X       | X    |     |    |    |     |     |     |     |     |     |    |
| Tumor evaluationm                                                                                                                                                                                                                                                                                                                                                                         | Xm                                             | Xm                                                           | Xm           | Xm      |      |     |    |    |     |     |     |     |     |     |    |
| MD/RN Phone calln                                                                                                                                                                                                                                                                                                                                                                         | Xn                                             | Xo                                                           |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Mandatory fresh pretreatment tumor  biopsy for all breast cancer and NSCLC patients                                                                                                                                                                                                                                                                                                       | X                                              |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Most recent metastatic tumor tissue                                                                                                                                                                                                                                                                                                                                                       | Xp                                             |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |
| sample for all patients Optional on-treatment or end-oftreatment fresh core tumor biopsyq                                                                                                                                                                                                                                                                                                                                                                                           | Xq                                             | Xq                                                           |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Loperamide antidiarrheal treatmentr                                                                                                                                                                                                                                                                                                                                                       | Administered orally daily                      | Administered orally as needed (not to  exceed 16 mg per day) |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Patient Diarys                                                                                                                                                                                                                                                                                                                                                                            | X                                              |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Concomitant therapy                                                                                                                                                                                                                                                                                                                                                                       | Collected continuously throughout study period |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Adverse eventst                                                                                                                                                                                                                                                                                                                                                                           | Collected continuously throughout study period |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |
| Patient Reported Outcomesu                                                                                                                                                                                                                                                                                                                                                                | Xu                                             | Xu                                                           | Xu           | Xu      | Xu   | Xu  |    |    |     |     |     |     |     |     |    |
| Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; C1D1 = Cycle 1 Day 1; cfDNA = cell-fee DNA; CT = computerized  tomography; D = Day; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FFPE = formalin-fixed paraffin embedded; Hb = hemoglobin; Hct = hematocrit; |                                                |                                                              |              |         |      |     |    |    |     |     |     |     |     |     |    |  
ICF = informed consent form; IP = Investigational Product; LDH = lactate dehydrogenase; MD = medical doctor; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition scan; NSCLC = non-small cell lung cancer; PD = progressive disease; PET = positron emission tomography; RECIST = Response Evaluation Criteria in Solid Tumors; RBC = red blood cells; RN = registered nurse; W = week; WBC = white blood cell a. End of treatment (EOT) follow-up assessments will be conducted 28 days (+14 days) after last administration of IP(s). AEs must be followed for 28 days after last administration of IP(s).  
b. Follow-up visits will occur every 2 cycles (8 weeks ± 7 days) for patients discontinuing treatment for any reason other than disease progression until objective disease progression is reported per RECIST v 1.1 (or other response criteria). After disease progression, all patients will be followed every 12 weeks for survival and anticancer medication taken will be collected.  
c. Collect chronic medical condition and medical history of significance (including smoking history only for lung cancer patients), or symptoms experienced during the previous 30 days and those ongoing at the time of screening, and any medical conditions that require medication. Identify start of current medical conditions by at least providing the year of onset.  
d. Physical examination may be delegated and performed by a properly trained nurse practitioner, physician's assistant, or equivalent. Full physical examination at screening, C1D1 and thereafter should be a detailed/brief (system-guided) physical examination to evaluate any clinically significant abnormalities; including worsening of medical history conditions. Vital signs include pulse, blood pressure, temperature
(in Celsius) and respiration rate taken before dosing. Also includes height (screening only) and weight.  
e. Physical examination / ECOG status does not need to be repeated if performed within 72 hours prior to C1D1. f. All neratinib monotherapy cohorts will have ECGs performed at baseline and at end of treatment only. g. Laboratory urinalysis or by urine dipstick (blood, protein, glucose, and microscopic examination, if abnormal). Urine or serum pregnancy test only for women of child-bearing potential (at screening, and to be repeated only if performed outside 72 hours of C1D1).  
h. Hematology panel: Hct, Hb, platelet count, RBC count, and WBC count with differential. Serum chemistry: albumin, alkaline phosphatase, ALT, AST, BUN, calcium, chloride, serum creatinine, glucose (nonfasting), LDH, magnesium, phosphorous, potassium, serum cholesterol (non-fasting), total bilirubin, total protein, and sodium. Following C1, laboratory tests may take place ± 2 days before Day 1.  
i. Laboratory assessments are not required on C1D1 if previously obtained within 72 hours prior to C1D1 as part of screening, with no clinically significant findings.  
j. Plasma collection for cfDNA biomarker analysis at screening (if collected on C1D1, it has to be done prior to the first IP dose), at the beginning of Week 9 (ORRfirst), and every 2 cycles (8 weeks ± 7 days)
thereafter, and during the EOT visit.  
k. Whole blood sample for research (single collection) obtained during study, preferably during screening or within the first cycle of therapy.  
l. Neratinib and fulvestrant administration performed as described in Section 5.1.  
m. Tumor assessment at screening should occur within 4 weeks of C1D1, as appropriate. Post-treatment disease assessment by CT or PET/CT scan or MRI of the chest, abdomen and pelvis, as appropriate, will be conducted at the beginning of Week 9 (ORRfirst), and every 2 cycles (8 weeks ± 7 days) until 1 year, and annually (once per year). Following one year on therapy, scans may move to every 3 cycles for nontrastuzumab containing regimens. Following two years on therapy, scans may move to every 4 cycles for non-trastuzumab containing regimens. The scans must be obtained and reviewed prior to start of the next cycle. CT or PET/CT or MRI should be done only at EOT if not done within the previous 4 weeks, or if required to confirm an objective response. Overall response will be scored by independent assessment and by the Investigator according to RECIST v1.1 using the algorithms defined in the protocol. Tumor assessments should be continued every 2 cycles (8 weeks ± 7 days) for any patients ending therapy for any reason other than radiological PD. For patients who enrolled prior to Amendment 6, the same method of measurement (eg PET/CT) and same method of disease assessment (eg metabolic response by PET Response Criteria) should continue through final assessments.  
n. Phone call to patient 1 day, 2 days, and 3 days after the first dose of neratinib (C1D1) to check on diarrhea symptoms and patient compliance with anti-diarrheal therapy. o. AEs, SAEs, and clinically significant abnormal laboratory results should be followed for 28 days after the last dose of IP(s); this information may be collected at the EOT visit or via phone call. Follow patients via phone call every 12 weeks (±14 days) after disease progression to monitor survival.  
p. Archival tissue sample obtained during screening or within the first cycle of therapy. In cases where a patient is enrolled based on a documented HER mutation derived from a cfDNA specimen (ie, liquid biopsy),
a mandatory archival FFPE or fresh-tumor biopsy should be submitted for retrospective central confirmation of the mutation.  
q. Optional fresh core tumor biopsy from all patients upon progression of disease.  
r. Loperamide antidiarrheal treatment should be dispensed with the initial supply of neratinib. 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.  
s. Patient Diary will be provided by the Investigator for the patient to record daily study medication intake for every cycle, and frequency and management of diarrhea in the first 2 cycles. t. Symptoms should be assessed from signing of ICF and during any protocol visit that includes a physical examination. AEs should be followed for 28 days after last administration of IP(s).  
u. FACT-G will be performed at Screening, C1D1 and at the beginning of each cycle for up to 6 months or EOT, whichever comes first.
table of contents
appendix 2 eastern cooperative oncology

| Description                                                                                                                                         | Grade   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------|---------|
| Fully active, able to carry on all pre-disease performance without  restriction.                                                                    | 0       |
| Restricted in physically strenuous activity, but ambulatory and able to  carry out work of a light or sedentary nature, ie, light housework, office | 1       |
| work. Ambulatory and capable of all self-care but unable to carry out any work  activities. Up and about more than 50% of waking hours.             | 2       |
| Capable of only limited self-care, confined to bed or chair more than  50% of waking hours.                                                         | 3       |
| Completely disabled. Cannot carry on any self-care. Totally confined to  bed or chair.                                                              | 4       |
| Dead                                                                                                                                                | 5       |
table of contents
appendix 3 inhibitors and inducers

| P450 ISOENZYMES CYP3A4 Inducers   |                              |                             |                |
|-----------------------------------|------------------------------|-----------------------------|----------------|
| Carbamazepine                     | Macrolide Antibiotics        | Rifabutin                   |                |
| Efavirenz                         | Phenobarbital                | Rifampin                    |                |
| Glucocorticoids                   | Phenylbutazone               | Rifapentine                 |                |
|                                   | Dexamethasone                | Phenytoin                   | Sulfinpyrazone |
|                                   | Prednisone                   | Primidone CYP3A4 Inhibitors |                |
| Amprenavir                        | Grapefruit Juice             | Propranolol                 |                |
| Anastrozole                       | Indinavir                    | Quinine                     |                |
| Cimetidine                        | Itraconazole                 | Quinidine                   |                |
| Clarithromycin                    | Ketoconazole                 | Ranitidine                  |                |
| Clotrimazole                      | Mibefradil                   | Ritonavir                   |                |
| Danazol                           | Miconazole                   | Saquinavir                  |                |
| Delavirdine                       | Mirtazapine (weak)           | Sertraline                  |                |
| Diethyldithiocarbamate            | Nefazodone                   | Sildenafil (weak)           |                |
| Diltiazem                         | Nelfinavir                   | Troglitazone                |                |
| Erythromycin                      | Nevirapine                   | Troleandomycin              |                |
| Fluconazole                       | Norfloxacin                  | Zafirlukast                 |                |
| Fluoxetine                        | Norfluoxetine                |                             |                |
| Fluvoxamine                       | Paroxetine CYP3A5-7 Inducers |                             |                |
| Phenobarbital                     | Primidone                    | Rifampin                    |                |
| Phenytoin                         | CYP3A5-7 Inhibitors          |                             |                |
| Clotrimazole                      | Metronidazole                | Troleandomycin              |                |
| Ketoconazole                      | Miconazole                   |                             |                |  
APPENDIX 3. **INHIBITORS AND INDUCERS OF THE CYTOCHROME P460**  
ISOENZYMES (CONTINUED)  
| ISOENZYMES (CONTINUED) CYP2D6 Substrate                                                                    |                       |                      |               |
|------------------------------------------------------------------------------------------------------------|-----------------------|----------------------|---------------|
| Carvedilol                                                                                                 | Maprotiline           | Selegiline           |               |
| Chloroquine (possible)                                                                                     | Methamphetamine       | Sertraline           |               |
| Chlorpromazine                                                                                             | Metoprolol            | Sparteine            |               |
| Citalopram                                                                                                 | Mexiletine (major)    | Tamoxifen            |               |
| Clozapine                                                                                                  | Mirtazapine           | Thioridazine         |               |
| Codeine                                                                                                    | Morphine              | Timolol              |               |
| Cyclobenzaprine                                                                                            | Olanzapine            | Tolterodine (major)  |               |
| Debrisoquin                                                                                                | Ondansetron           | Tramadol             |               |
| Delavirdine                                                                                                | Oxaminiquine          | Trazodone            |               |
| Dexfenfluramine                                                                                            | Oxycodone             | TCAs (hydroxylation) |               |
| Dextromethorphan                                                                                           | Paroxetine            |                      | Amitriptyline |
| Dolasetron                                                                                                 | Penbutolol            |                      | Clomipramine  |
| Donepezil                                                                                                  | Pentazocine           |                      | Desipramine   |
| Encainide                                                                                                  | Perphenazine          |                      | Doxepin       |
| Flecainide                                                                                                 | Phenformin            |                      | Imipramine    |
| Fluoxetine                                                                                                 | Primaquine (possible) |                      | Nortriptyline |
| Fluphenazine                                                                                               | Propafenone           | Trimipramine         |               |
| Halofantrine                                                                                               | Propoxyphene          | Venlafaxine          |               |
| Haloperidol                                                                                                | Propranolol (minor)   | Ziprasidone          |               |
| Hydrocodone                                                                                                | Risperidone           | Zolpidem             |               |
| Hydroxyamphetamine                                                                                         | Ritonavir             |                      |               |
| Labetalol                                                                                                  | Ropivacaine           |                      |               |
| Source: Tatro DS, Drug Interaction Facts: The Authority on Drug Interactions. Wolters Kluwer Health, 2012. |                       |                      |               |
table of contents
appendix 4 substrates and inhibitors

| P-glycoprotein Substrates Amiodarone (eg, Cordarone)                                                       | Fluphenazine (eg, Prolixin)   | Progesterone (eg, Prometrium)   |
|------------------------------------------------------------------------------------------------------------|-------------------------------|---------------------------------|
| Chlorpromazine (eg, Thorazine)                                                                             | Hydrocortisone (eg, Cortef)   | Promethazine (eg, Phenergan)    |
| Clarithromycin (eg, Biaxin)                                                                                | Indinavir (Crixivan           | Quinidine                       |
| Cyclosporine (eg, Neoral)                                                                                  | Itraconazole (eg, Sporanox)   | Reserpine                       |
| Dactinomycin (Cosmegen)                                                                                    | Ketoconazole (eg, Nizoral)    | Ritonavir (Norvir)              |
| Daunorubicin (eg, Cerubidine)                                                                              | Lidocaine (eg, Xylocaine)     | Saquinavir (eg, Fortovase)      |
| Dexamethasone (eg, Decadron)                                                                               | Loperamide (eg, Imodium)      | Sirolimus (Rapamune)            |
| Digoxin (eg, Lanoxin)                                                                                      | Lovastatin (eg, Mevacor)      | Tacrolimus (Prograf)            |
| Diltiazem (eg, Cardizem)                                                                                   | Mifepristone (Mifeprex)       | Tamoxifen (eg, Nolvadex)        |
| Doxorubicin (eg, Adriamycin)                                                                               | Mitoxantrone (Novantrone)     | Teniposide (Vumon)              |
| Erythromycin (eg, Ery-Tab)                                                                                 | Nelfinavir (Viracept)         | Testosterone Delatestryl)       |
| Estradiol (eg, Estrace)                                                                                    | Nicardapine (eg, Cardene)     | Trifluoperazine                 |
| Etoposide (eg, Vepesid)                                                                                    | Nifedipine (eg, Procardia)    | Verapamil (eg, Calan)           |
| Felodipine (Plendil)                                                                                       | Ondansetron (Zofran)          | Vinblastine (eg, Velban)        |
| Fexofenadine (Allegra)                                                                                     | Paclitaxel (eg, Taxol)        | Vincristine (eg, Vincasar PFS)  |
| P-glycoprotein Inhibitors Amiodarone (eg, Cordarone)                                                       | Indinavir (Crixivan)          | Quinidine                       |
| Atorvastatin (Lipitor)                                                                                     | Itraconazole (eg, Sporanox)   | Reserpine                       |
| Chlorpromazine (eg, Thorazine)                                                                             | Ketoconazole (eg, Nizoral)    | Ritonavir (Norvir)              |
| Clarithromycin (eg, Biaxin)                                                                                | Lidocaine (eg, Xylocaine)     | Saquinavir (eg, Fortovase)      |
| Cyclosporine (eg, Neoral)                                                                                  | Mifepristone (Mifeprex)       | Tacrolimus (Prograf)            |
| Diltiazem (eg, Cardizem)                                                                                   | Nelfinavir (Viracept)         | Tamoxifen (eg, Nolvadex)        |
| Erythromycin (eg, Ery-Tab)                                                                                 | Nicardipine (eg, Cardene)     | Testosterone (Delatestryl)      |
| Felodipine (Plendil)                                                                                       | Nifedipine (eg, Procardia)    | Trifluoperazine                 |
| Fluphenazine (eg, Prolixin)                                                                                | Progesterone (eg, Prometrium) | Verapamil (eg, Calan)           |
| Hydrocortisone (eg, Cortef)                                                                                | Propranolol (eg, Inderal)     |                                 |
| Source: Tatro DS, Drug Interaction Facts: The Authority on Drug Interactions. Wolters Kluwer Health, 2012. |                               |                                 |  
APPENDIX 5 **DRUGS ASSOCIATED WITH RISK OF QT/QTC**  
PROLONGATION LEADING **TO TORSADE DE**  
POINTES  
| POINTES                                                               |                                              |                          |
|-----------------------------------------------------------------------|----------------------------------------------|--------------------------|
| Drugs Reported to Prolong QT Interval Analgesics Celecoxib (Celebrex) | Methadone (eg, Dolophine, Methadose)         |                          |
| Anesthetic agents Enflurane (eg, Ethrane)                             | Halothane                                    |                          |
| Isoflurane (eg, Forane) Antiarrhythmic agents Class IA                | Class III                                    |                          |
| Disopyramide (eg, Norpace)*                                           | Amiodarone (eg, Cordarone)*b                 |                          |
| Procainamide (eg, Procanbid)*                                         | Bretylium*                                   |                          |
| Quinidine*                                                            | Dofetilide (Tikosyn)*b                       |                          |
| Class IC                                                              | Ibutilide (Corvert)*b                        |                          |
| Flecainide (eg, Tambocor)*a                                           | Sotalol (eg, Betapace)*b                     |                          |
| Propafenone (eg, Rythmol)*b                                           |                                              |                          |
| Anticonvulsants Felbamate (Felbatol)*                                 | Fosphenytoin (Cerebyx)                       |                          |
| Antiemetics Dolasetron (Anzemet)b                                     | Droperidol (eg, Inapsine)*b                  | Ondansetron (Zofran)     |
| Antihistamines Desloratadine (Clarinex)b (overdose)                   | Fexofenadine (Allegra)                       |                          |
| Diphenhydramine (eg, Benadryl)                                        | Hydroxyzine (Atarax)                         |                          |
| Anti-infectives Amantadine (eg, Symmetrel)*                           | Macrolides and related antibiotics           |                          |
| Antimalarials                                                         | Azithromycin (eg, Zithromax)                 |                          |
| Mefloquine (eg, Lariam)b                                              | Clarithromycin (eg, Biaxin)*b                |                          |
| Quinine*                                                              | Erythromycin (eg, Ery-Tab, EES)*b            |                          |
| Antivirals                                                            | Telithromycin (Ketek)b                       |                          |
| Efavirenz (Sustiva)*                                                  | Troleandomycin                               |                          |
| Azole antifungal agents                                               | Pentamidine (eg, Pentam 300, Nebupent)*      |                          |
| Fluconazole (eg, Diflucan)*b                                          | Quinolones                                   |                          |
| Itraconazole (eg, Sporanox)                                           | Gatifloxacin (eg, Tequin)*b                  |                          |
| Ketoconazole (eg, Nizoral)                                            | Levofloxacin (eg, Levaquin)*a, b             |                          |
| Voriconazole (Vfend)b                                                 | Moxifloxacin (eg, Avelox)b                   |                          |
| Chloroquine (eg, Aralen)*                                             | Ofloxacin (eg, Floxin)*b                     |                          |
| Clindamycin (eg, Cleocin)                                             | Sparfloxacin (Zagam)b                        |                          |
| Foscarnet (Foscavir)                                                  | Trimethoprim/sulfamethoxazole (eg, Bactrim)* |                          |
| Antineoplastics Arsenic trioxide (Trixenox)*b                         | Doxorubicin (eg, Adriamycin)                 | Tamoxifen (eg, Nolvadex) |
| Bronchodilators Albuterol (eg, Proventil)b                            | Salmeterol (Serevent)b                       |                          |
| Formoterol (Foradil)b                                                 | Terbutaline (eg, Brethine)b                  |                          |
| Isoproterenol (eg, Isuprel)                                           |                                              |                          |  
| PUMA-NER-5201                                                                                                                                        | AMENDMENT 7                                       |                               |
|------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------|-------------------------------|
| Drugs Reported to Prolong QT Interval Calcium channel blockers Isradipine (DynaCirc)                                                                 | Nicardipine (eg, Cardene)                         |                               |
| Contrast media Ionic contrast media*                                                                                                                 | Non-ionic contrast media: Iohexol (Omnipaque)     |                               |
| Corticosteroids Prednisolone (eg, Prelone)                                                                                                           | Prednisone (eg, Deltasone)*                       |                               |
| Diuretics Furosemide (eg, Lasix)                                                                                                                     | Indapamide (eg, Lozol)                            |                               |
| Gastrointestinal agents Cisapride (Propulsid)*b                                                                                                      | Famotidine (eg, Pepcid)*                          |                               |
| Immunosuppressants Tacrolimus (Protopic)*b (postmarketing) Miscellaneous Levomethadyl                                                                | Papaverine (eg, Pavaden three times daily [TID])* |                               |
| Moexipril/Hydrochlorothiazide (Uniretic)                                                                                                             | Probucol (Lorelco)*                               |                               |
| Octreotide (Sandostatin)b                                                                                                                            | Vasopressin (eg, Pitressin)*                      |                               |
| Oxytocin (eg, Pitocin; IV bolus) Psychotropics Droperidol (eg, Inapsine)*                                                                            | Primozide (Orap)*b                                | Trazodone (eg, Desyrel)       |
| Haloperidol (eg, Haldol)*                                                                                                                            | Quetiapine (Seroquel)b                            | Tricyclic antidepressants     |
| Lithium (eg, Eskalith)*                                                                                                                              | Risperidone (Risperdal)b (overdose)               | Amitriptyline*                |
| Maprotiline*                                                                                                                                         | Serotonin Reuptake Inhibitors                     | Clomipramine                  |
| (SRIs)                                                                                                                                               | (eg, Anafranil)                                   |                               |
| Phenothiazines                                                                                                                                       | Citalopram (eg, Celexa)*                          | Desipramine  (eg, Norpramin)* |
| Chlorpromazine                                                                                                                                       | Fluoxetine (eg, Prozac)*a                         | Doxepin (eg, Sinequan)*       |
| (eg, Thorazine)* Fluphenazine                                                                                                                        | Paroxetine                                        | Imipramine (eg, Tofranil)*    |
| (eg, Prolixin)*                                                                                                                                      | (eg, Paxil)*                                      |                               |
| Perphenazine                                                                                                                                         | Sertraline (Zoloft)*a, b                          | Nortriptyline                 |
| (postmarketing)                                                                                                                                      | (eg, Pamelor)                                     |                               |
| Thioridazine (Mellaril)*b                                                                                                                            | Venlafaxine (Effexor)b  (postmarketing)           |                               |
| Trifluopherazine                                                                                                                                     |                                                   |                               |
| Serotonin 5-HT1 agonists Naratriptan (Amerge)                                                                                                        | Sumatriptan (Imitrex)b                            | Zolmitriptan (Zomig)b         |
| Skeletal muscle relaxants Tizanidine (eg, Zanaflex)b (animals) *  Drugs for which Torsades de Pointes has also been reported. a  Association unclear |                                                   |                               |
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appendix 6 recist v1.1 criteria

Only patients with measurable disease at baseline should be included in this study. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criterion. Note: Lesions are either measurable or nonmeasurable using the criteria provided below. The term "evaluable" in reference to measurability provides neither additional meaning nor accuracy and will not be used.
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measurable disease

Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:  
- 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). - 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable).  
- 20 mm by chest X-ray.
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nonmeasurable disease

- Small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to
<15 mm short axis).  
- Truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques.
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target lesions

When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and will be recorded and measured at baseline (this means in instances where patients have only one or two organ sites involved a maximum of two and four lesions respectively will be recorded). Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. Lymph nodes merit special mention since they are normal anatomical structures which may be visible by imaging even if not involved by tumor. Pathological nodes which are defined as measurable and may be identified as target lesions must meet the criterion of a short axis of ≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the node measurement. All other pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered nontarget lesions. Nodes that have a short axis <10 mm are considered non-pathological and should not be recorded or followed. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then as noted above, only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease.
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nontarget lesions

All other lesions (or sites of disease) including pathological lymph nodes should be identified as nontarget lesions and should also be recorded at baseline. Measurements are not required, and these lesions should be followed as 'present', 'absent', or in rare cases 'unequivocal progression' (more details to follow). In addition, it is possible to record multiple nontarget lesions involving the same organ as a single item on the case record form (eg, 'multiple enlarged pelvic lymph nodes' or 'multiple liver metastases').
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guidelines for evaluation of measurable

All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline evaluations should be performed as close as possible to the treatment start and never more than 28 days before the beginning of the treatment.
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method of assessment

The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging based evaluation should always be done rather than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and ≥10 mm diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, documentation by color photography including a ruler to estimate the size of the lesion is suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be undertaken since it is more objective and may also be reviewed at the end of the study. Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung. CT, MRI: CT is the best currently available and reproducible method to measure lesions selected for response assessment. This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (eg, for body scans). Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. However, they can be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in studies where recurrence following CR or surgical resection is an endpoint. Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If markers are initially above the upper normal limit, however, they must normalize for a patient to be considered in CR. Because tumor markers are disease specific, instructions for their measurement should be incorporated into protocols on a disease specific basis. In addition, the Gynecologic Cancer Intergroup has developed CA125 progression criteria which are to be integrated with objective tumor assessment for use in first-line studies in ovarian cancer. Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases if required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where known residual benign tumors can remain). When effusions are known to be a potential adverse effect of treatment (eg, with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can be considered if the measurable tumor has met criteria for response or SD in order to differentiate between response (or SD) and PD.
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evaluation of target lesions

This section provides the definitions of the criteria used to determine objective tumor response for target lesions. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes
(whether target or nontarget) must have reduction in short axis to <10 mm.  
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
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evaluation of nontarget lesions

This section provides the definitions of the criteria used to determine the tumor response for the group of nontarget lesions. While some nontarget lesions may actually be measurable, they need not be measured and instead should be assessed only qualitatively at the time points specified in the protocol. Complete Response (CR): Disappearance of all nontarget lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).  
Non-CR/Non-PD (stable disease): Persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD): Unequivocal progression of existing nontarget lesions. (Note: the appearance of one or more new lesions is also considered progression).  
| Target Lesions                                                                                                               | Nontarget Lesions           | New Lesions   | Overall Response   |
|------------------------------------------------------------------------------------------------------------------------------|-----------------------------|---------------|--------------------|
| CR                                                                                                                           | CR                          | No            | CR                 |
| CR                                                                                                                           | SD                          | No            | PR                 |
| CR                                                                                                                           | Not evaluated               | No            | PR                 |
| PR                                                                                                                           | Non-PD or not all evaluated | No            | PR                 |
| SD                                                                                                                           | Non-PD or not all evaluated | No            | SD                 |
| Not all evaluated                                                                                                            | Non-PD                      | No            | NE                 |
| PD                                                                                                                           | Any                         | Yes or No     | PD                 |
| Any                                                                                                                          | PD                          | Yes or No     | PD                 |
| Any                                                                                                                          | Any                         | Yes           | PD                 |
| Abbreviations: CR: complete response; NE: not evaluated; PD: progressive disease; PR: partial response; SD: stable  disease. |                             |               |                    |
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table a6.1. evaluation criteria

Note: Patients with a global deterioration of health status requiring discontinuation of the IP (defined as neratinib monotherapy or neratinib combination per indication) without objective evidence of disease progression at that time should be classified as having "symptomatic deterioration." Every effort should be made to document the objective progression, even after discontinuation of the IP. In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the evaluation of CR depends on this determination, it is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the CR status.
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confirmatory measurement/duration of response confirmation

In nonrandomized studies where response is the primary endpoint, confirmation of PR and CR is required to ensure responses identified are not the result of measurement error. This will also permit appropriate interpretation of results in the context of historical data where response has traditionally required confirmation in such studies. However, in all other circumstances, ie, in randomized studies (phase 2 or 3) or studies where SD or progression are the primary endpoints, confirmation of response is not required since it will not add value to the interpretation of study results. However, elimination of the requirement for response confirmation may increase the importance of central review to protect against bias, in particular in studies which are not blinded. In the case of SD, measurements must have met the SD criteria at least once after study entry at a minimum interval (not less than 6 weeks) that is defined in the study protocol.
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duration of overall response

The duration of overall response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively documented (taking as reference for PD the smallest measurements recorded on study). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.
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duration of stable disease

Stable disease is measured from the start of the treatment (in randomized studies, from date of randomization) until the criteria for progression are met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the reference for calculation of PD). The clinical relevance of the duration of SD varies in different studies and diseases. If the proportion of patients achieving SD for a minimum period of time is an endpoint of importance in a particular study, the protocol should specify the minimal time interval required between two measurements for determination of SD. Note: The DOR and SD as well as the PFS are influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to define a standard follow-up frequency. The frequency should take into account many parameters including disease types and stages, treatment periodicity and standard practice. However, these limitations of the precision of the measured endpoint should be taken into account if comparisons between studies are to be made.
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optimal duration of treatment with

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. Assessment of progression may be challenging because of the combination of difficulty in interpreting imaging and the indolent nature of HR+ disease in some patients. Treatment should focus on patient outcomes and symptoms. Tumor flare reactions (increase in tumor-related symptoms) can occur, particularly with tamoxifen and estradiol; were observed shortly after beginning a new endocrine treatment; and can be confused with disease progression. Treatmentrelated toxicity may be a reason to change therapy Patient outcomes were not improved by changing therapy based solely on tumor markers or circulating tumor cells.  
Sources: Boellaard, et al, 2010; Brucher et al, 2001; Costelloe et al 2009; Costelloe, et al; 2010; Dose Schwarz et al, 2005; Gayed et al, 2004; Hawkins et al 2009; Hellwig et al, 2004; Mac Manus et al, 2003; Rugo, et al; 2016; Shankar, et al; 2006; Smith et al, 2000; Stroobants et al, 2003; Swisher et al, 2004; Van den Abbeele et al, 2008; Wahl, et al; 2009; Weber et al, 2006; Wieder et al, 2004; Young, et al; 1999
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appendix 7 specific guidance on

In the context of this study, the word *mutation* refers to an alteration of somatic, tumorassociated genomic DNA sequence that alters the protein coding region in a nonconserved manner, and may range from single base point mutations to larger regions of inserted, repeated or deleted genomic DNA sequence.  
A list of known activating or potentially activating somatic mutations in *ERBB2* is provided in Table A7.1 and in *EGFR* exon 18 in Table A.7.2. The mutations in this list have been characterized in the scientific literature (PubMed) and/or identified in two or more cases as detailed in publicly available databases (COSMIC, cBioPortal for Cancer Genomics). In cases where a patient is enrolled based on a documented *ERBB* mutation derived from a cfDNA specimen (ie, liquid biopsy), a mandatory archival FFPE or fresh-tumor biopsy should be submitted for retrospective central confirmation of the mutation.  
| Table A7.1.                     | Eligible ERBB2 Mutations   |                           |
|---------------------------------|----------------------------|---------------------------|
| 1 Letter Amino Acid             | 3 Letter Amino Acid        | Other Common Nomenclature |
| Nomenclature                    | Nomenclature               |                           |
| G309A                           | Gly309Ala                  |                           |
| G309E                           | Gly309Glu                  |                           |
| S310F                           | Ser310Phe                  |                           |
| S310Y                           | Ser310Tyr                  |                           |
| S653C                           | Ser635Cys                  |                           |
| V659E                           | Val659Glu                  |                           |
| G660D                           | Gly660Asp                  |                           |
| V697L                           | Val697Leu                  |                           |
| T733I                           | Thr733Ile                  |                           |
| L755S                           | Leu755Ser                  |                           |
| L755P                           | Leu755Pro                  |                           |
| L755_T759del                    | Leu755_Thr759del           | ∆LRENT                    |
| I767M                           | Ile767Met                  |                           |
| D769Y                           | Asp769Tyr                  |                           |
| D769H                           | Asp769His                  |                           |
| D769N                           | Asp769Asn                  |                           |
| Y772_A775dup                    | Tyr772_Ala755dup           | A775_G776insYVMA          |
| G776C                           | Gly776Cys                  |                           |
| G776V                           | Gly776Val                  |                           |
| G776VinsC/VGC/other             | Gly776insCys/other         |                           |
| Other exon 20 insertions  V777L | Val777Leu                  |                           |
| G778_P780dup                    | Gly778_Pro780dup           | P780_Y781insGSP           |
| L841V                           | Leu841Val                  |                           |
| V842I                           | Val842Ile                  |                           |
| L869R                           | Leu869Arg                  |                           |
| L866M                           | Leu869Met                  |                           |
| H878Y                           | His878Tyr                  |                           |
| R896C                           | Arg896Cys                  |                           |
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table a7.1. eligible erbb2 mutations

Neratinib Tablets (PB-272) 03-FEB-2021 PUMA-NER-5201 AMENDMENT 7 Table A7.2. Eligible *EGFR* **exon 18 Mutations**  
| EGFR exon 18  E709X  E709 indel  G719X  G719 indel   |
|------------------------------------------------------|  
APPENDIX 8 **PATIENT-REPORTED HEALTH OUTCOMES**
ASSESSMENT (FACT-G):
fact-g (version 4)
table a7.1. eligible erbb2 mutations

Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
GE1 GE2 GE3 GE4 GES
00  
| EMOTIONAL WELL-BEING                                          | Not   | A little   | Some-   | Quite   | Very   |
|---------------------------------------------------------------|-------|------------|---------|---------|--------|
| at all                                                        | what  | a bit      | much    |         |        |
| bit                                                           |       |            |         |         |        |
| I feel sad .                                                  | 0     | 2          | 3       | 4       |        |
| 1                                                             |       |            |         |         |        |
| I am satisfied with how I am coping with my illness.......... | 0     | 1          | 2       | 3       | 4      |
| I am losing hope in the fight against my illness              | 0     | 1          | 2       | 3       | 4      |
| I feel nervous                                                | 0     | 1          | 2       | 3       | 4      |
| I worry about dying                                           | 2     | 3          |         |         |        |
| 0                                                             | l     | 4          |         |         |        |
| I worry that my condition will get worse .                    | 0     | l          | 2       | 3       | 4      |  
Very much 4 4 4 4 4 4 4 GF1  
| FUNCTIONAL WELL-BEING                              | Not   |
|----------------------------------------------------|-------|
| at all                                             |       |
| I am able to work (include work at home) .         | 0     |
| My work (include work at home) is fulfilling       | 0     |
| I am able to enjoy life.                           | 0     |
| I have accepted my illness                         | 0     |
| I am sleeping well .                               | 0     |
| I am enjoying the things I usually do for fun      | 0     |
| I am content with the quality of my life right now | 0     |  
GF2 GF3 GF4 GS
GF6 GF7 Eaglish (Universal)
Copyright  1987, 1997.  
| A little   | Some-   | Quite   |
|------------|---------|---------|
| what       | a bit   |         |
| bit        |         |         |
| 1          | 2       | 3       |
| i          | 2       | 3       |
| l          | 2       | 3       |
| 1          | 2       | 3       |
| i          | 2       | 3       |
| 1          | 2       | 3       |
| l          | 2       | 3       |  
16 November 2007