a phase ii study of
11.0 study calendar

Evaluations for pre-registration should be conducted within 8 weeks prior to pre-registration and specimen submission. Evaluations for registration should be conducted within 2 weeks prior to registration, with the following exceptions: echocardiogram, scans, and x-rays, which should be performed within 4 weeks of registration. Study drug therapy should start within 7 days of registration.  
Screening Through Cycle 1  
Pre-ScreeningW  
-56 to 0 days  
| should be performed within 4 weeks of registration. Study drug therapy should start within 7 days of registration.  Screening Through Cycle 1 Pre-ScreeningW -56 to 0 days Screening -14 to 0 days  unless otherwise  noted C1D1 (- 7) C1D2 C1D3 C1D4   | C1D8 (+/- 1)                                                        | C1D15 (+/- 1)                                                       | C1D22 (+/- 1)                                                       |    |    |    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------|---------------------------------------------------------------------|---------------------------------------------------------------------|----|----|----|
| Informed Consent                                                                                                                                                                                                                                        | X                                                                   | XV                                                                  |                                                                     |    |    |    |
| Medical History                                                                                                                                                                                                                                         | X                                                                   | X                                                                   |                                                                     |    |    |    |
| Physical Exam w/ECOG                                                                                                                                                                                                                                    | XI                                                                  | X                                                                   | X                                                                   | X  | X  | X  |
| Vital SignsA                                                                                                                                                                                                                                            | X                                                                   | X                                                                   | XL                                                                  | XL | XL |    |
| Safety Phone CallK                                                                                                                                                                                                                                      | X                                                                   | X                                                                   | X                                                                   |    |    |    |
| Adverse Events                                                                                                                                                                                                                                          | X-----------------------------------------------------------------X |                                                                     |                                                                     |    |    |    |
| CBC w/Differential                                                                                                                                                                                                                                      | X                                                                   | X                                                                   | XM                                                                  |    |    |    |
| Blood Chemistry                                                                                                                                                                                                                                         | X                                                                   | X                                                                   | XM                                                                  |    |    |    |
| Pregnancy TestH                                                                                                                                                                                                                                         | X                                                                   |                                                                     |                                                                     |    |    |    |
| Blood for ResearchS                                                                                                                                                                                                                                     | X                                                                   | X                                                                   |                                                                     |    |    |    |
| ECG                                                                                                                                                                                                                                                     | X                                                                   |                                                                     |                                                                     |    |    |    |
| Echocardiogram or MUGAC                                                                                                                                                                                                                                 | XE                                                                  |                                                                     |                                                                     |    |    |    |
| Tumor Assessment (CT or MRI)D                                                                                                                                                                                                                           | XE                                                                  |                                                                     |                                                                     |    |    |    |
| Tumor Biopsy (optional)                                                                                                                                                                                                                                 | XO                                                                  |                                                                     |                                                                     |    |    |    |
| Archival Tumor                                                                                                                                                                                                                                          | XU                                                                  | XT                                                                  |                                                                     |    |    |    |
| HER2 Mutation Report                                                                                                                                                                                                                                    | XB                                                                  |                                                                     |                                                                     |    |    |    |
| Patient Instructions for Diarrhea  Management (Appendix C)                                                                                                                                                                                              | X                                                                   |                                                                     |                                                                     |    |    |    |
| NeratinibN                                                                                                                                                                                                                                              | X-----------------------------------------------------------------X |                                                                     |                                                                     |    |    |    |
| FulvestrantN, R                                                                                                                                                                                                                                         | X                                                                   | X                                                                   |                                                                     |    |    |    |
| Medication Diary (Appendix B)                                                                                                                                                                                                                           | X-----------------------------------------------------------------X |                                                                     |                                                                     |    |    |    |
| Concomitant Medications                                                                                                                                                                                                                                 | X                                                                   | X-----------------------------------------------------------------X |                                                                     |    |    |    |
| Serious Adverse Events                                                                                                                                                                                                                                  | XJ                                                                  | XJ                                                                  | X-----------------------------------------------------------------X |    |    |    |
| Pre-Registration                                                                                                                                                                                                                                        | Registration                                                        |                                                                     |                                                                     |    |    |    |  
| Cycle 2 Through End of Study              |                                                                                                    |          |    |    |    |
|-------------------------------------------|----------------------------------------------------------------------------------------------------|----------|----|----|----|
| C2D1 (+/- 3)                              | C3D1 (+/- 3)                                                                                       | Day 1 of |    |    |    |
| Subsequent  Even Cycles (+/- 3)           | Day 1 of                                                                                           |          |    |    |    |
| Subsequent  Odd Cycles (+/- 3)            | End of                                                                                             |          |    |    |    |
| Treatment (+ 7)                           | 30 Day Follow  Up (+/- 3)                                                                          |          |    |    |    |
| Physical Exam w/ECOG                      | X                                                                                                  | X        | X  | X  | X  |
| Vital Signs                               | X                                                                                                  | X        | X  | X  | X  |
| Adverse Events                            | X------------------------------------------------------------------------------------------------X |          |    |    |    |
| Follow Up Phone Call                      | X                                                                                                  |          |    |    |    |
| CBC w/Differential                        | X                                                                                                  | X        | X  | X  | X  |
| Blood Chemistry                           | X                                                                                                  | X        | X  | X  | X  |
| Blood for ResearchS                       | X                                                                                                  | X        | X  |    |    |
| Tumor Assessment (CT or MRI)D             | XF                                                                                                 | XF       |    |    |    |
| Tumor Biopsy (optional)                   | XP                                                                                                 |          |    |    |    |
| Medication Diary (Appendix B) NeratinibG  | X------------------------------------------------------------------------------X                   |          |    |    |    |
| FulvestrantR                              | X                                                                                                  | X        | X  | X  |    |
| Trastuzumab (or FDA approved biosimilar)Q | X----------------------------------------X                                                         |          |    |    |    |
| Concomitant Medications                   | X------------------------------------------------------------------------------------------------X |          |    |    |    |
| Serious Adverse Events                    | X------------------------------------------------------------------------------------------------X |          |    |    |    |
| A:                                        | Height to be recorded only at baseline                                                             |          |    |    |    |  
Physical Exam w/ECOG X X X X X Vital Signs X X X X X Adverse Events X------------------------------------------------------------------------------------------------X Follow Up Phone Call X CBC w/Differential X X X X X Blood Chemistry X X X X X  
Blood for ResearchS X X X  
Tumor Assessment (CT or MRI)D XF XF Tumor Biopsy (optional) XP  
Medication Diary (Appendix B)  
NeratinibG X------------------------------------------------------------------------------X FulvestrantR X X X X  
Trastuzumab (or FDA approved biosimilar)Q X----------------------------------------X  
Concomitant Medications X------------------------------------------------------------------------------------------------X Serious Adverse Events X------------------------------------------------------------------------------------------------X  
A: Height to be recorded only at baseline  
B: The sequencing report identifying the eligible HER2 mutation is required. C: Pre-registration and HER2 mutation testing, ECHO or MUGA is not required, but a patient with a known recent LVEF < LLN or with symptoms of congestive heart  
failure is not eligible for Pre-registration and HER2 mutation testing. ECHO or MUGA is required for all patients continuing to the treatment portion of the trial.  
D: CT of the chest, abdomen and pelvis with contrast is required for the study. If contrast could not be administered, CT of the chest without contrast, and MRI of abdomen  
and pelvis would be acceptable. The same method should be used at each evaluation. Patients with skin lesions should have photographs taken at baseline and each evaluation. Please have a CD copy of each radiology assessment at the completion of the exam or upload the image in the "drop box" specified in the secondary site instructions. Please use either the tumor measurement form in Appendix D for RECIST 1.1 response evaluation or an institutional RECIST 1.1 report for upload to the  
EDC.  
E: Within 28 days prior to Registration. F: Radiology test for tumor response assessment is to be performed at baseline and every 2 cycles (+/- 7 days). G: Neratinib is to be self-administered daily on each day of every 28-day cycle (+/- 3 days). Please see Section 6.1 for dosing instructions. H: Premenopausal women of childbearing potential only I: Only performance status is required J: Determined to be related to screening procedures. K: Safety calls to the patient are to be conducted 24, 48, and 72 hours after first dose administration and can be performed by study coordinator. L: Physical exam on C1D8, C1D15, and C1D22 may be performed by MD or research NP or RN. M: Cycle 1 Day 1 labs do not need to be repeated if done within 7 days of treatment.  
N: To accommodate calls to patients at 24, 48, and 72 hours post-drug initiation, the first dose of neratinib +/- fulvestrant could be started any time within one week following the C1D1 visit.  
O: Optional baseline biopsy must be performed within 4 weeks before C1D1 or on C1D1 prior to starting neratinib +/- fulvestrant. Please refer to Correlative Science Procedure Manual P: The biopsy at progression must occur prior to starting the next line of cancer therapy. Note that a clinical sequencing report will be provided to the treating physician in 3-4 weeks from Wash U. Please refer to the Correlative Science Procedure Manual.  
Q: May be administered if patient progresses on neratinib +/- fulvestrant; refer to Section 6.4.3 for dosing and schedule. The +/- 3 day window applies to all treatment days.  
Trastuzumab or any of the FDA approved commercially available biosimilar products for trastuzumab may be administered to patients based on their insurance requirements or institutional practice.  
R: In Part II ER+ cohorts, fulvestrant will be administered at a dose of 500 mg (2 x 250 mg injections) IM on Days 1 and 15 of Cycle 1, then on Day 1 of each subsequent cycle. Please see Section 6.3 for dosing instructions. Patients already on fulvestrant 500mg every 28 days prior to registration to the fulvestrant-treated cohort do not need to receive the loading dose on C1D15. In these patients, it is acceptable that C1D1 neratinib does not coincide with fulvestrant administration schedule per discretion of treating physician.  
S: Research blood is collected at baseline, on Cycle 1 day 15, Cycle 2 day 1, on Cycle 3 Day 1, followed by Day 1 of every other cycles (including Cycles 5, 7, etc), and EOT. Please refer to Correlative Science Procedure Manual.  
T: Due within 60 days of Registration. If sample was submitted for HER2 sequencing after pre-registration a new block may not be required. See Correlative Science Procedure Manual.  
U: See Correlative Science Procedure Manual for instructions for submitting archival tissue for HER2 sequencing V: Consent can be obtained earlier than the 14 day screening window W: Patients with known HER2 mutations (see Section 5.2) are not required to complete pre-screening and pre-registration.
a phase ii study of
12.0 data submission schedule

Case report forms with appropriate source documentation will be completed within 60 days of the schedule listed in this section. Electronic data management systems will be used in this trial in collaboration with the Institute for Informatics (I2) at Washington University. REDCap is a web-based clinical studies data management system that will be used for capture of clinical data from this trial. The case report forms developed for this trial will be transformed to electronic format. An electronic study calendar will drive the study's data collection workflow. Each center has access only to data from its own participants. Washington University, as the data coordinating center, has access to data from all sites. Contact the WUSTL study coordinator for instructions on how to request access.  
| Case Report Form                                                                                                                                       | Submission Schedule                                                                  |
|--------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|
| Only for patients being screened for HER2 mutation  at Washington University Pre-registration Consent Form Pathology Source Documents                  | Prior to HER2 mutation testing (send to main site registrar to confirm  eligibility) |
| Biospecimen Submission Form (CSPM Appendix 2) GPS Submission Form (CSPM Appendix 1)                                                                    | Sent with tumor sample                                                               |
| Biospecimen Submission Form (CPSM Appendix 2)                                                                                                          | Sent with peripheral blood                                                           |
| Consent Form Pathology Source Documents (only for patients who  were previously screened for HER2 mutation at  outside location) Eligibility Checklist | Prior to starting treatment                                                          |
| Within REDCap                                                                                                                                          |                                                                                      |
| Pre-Study Form Prior Therapy Form Vital Signs Form CBC Form Chemistries Form Tissue Collection Form                                                    | Enter prior to treatment start                                                       |
| Vital Signs Form CBC Form Chemistries Form Treatment Form                                                                                              | Enter within 2 week of the end of each cycle                                         |
| Peripheral Blood Collection Form                                                                                                                       | Due within 2 weeks of collection                                                     |
| Toxicity Form Concomitant Medications Form                                                                                                             | Continuous                                                                           |
| Treatment Summary Form                                                                                                                                 | Completion of treatment                                                              |
| Follow Up Form                                                                                                                                         | 30 Day follow up Baseline                                                            |
| Tumor Measurement Form                                                                                                                                 | End of every other cycle End of treatment                                            |
| MedWatch Form                                                                                                                                          | See Section 8.0 for reporting requirements                                           |  
Any queries generated by Washington University must be responded to within 14 days of receipt by the participating site. The Washington University research team will conduct a regular review of data status at all secondary sites, with appropriate corrective action to be requested as needed.
a phase ii study of
13.0 measurement of effect 13.1

For the purposes of this study, patients should be re-evaluated for response every 8 weeks (2 cycles). Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
a phase ii study of
13.2 disease parameters

Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Tumor lesions from a previously irradiated area may only be used as index lesions if they have demonstrated clear progression since completion of the radiation. Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. 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. 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 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. Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.
a phase ii study of
13.3 methods for evaluation of

All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. 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 is preferred to evaluation by 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
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If 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 (e.g. for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. 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, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008]. In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:  
- Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD
based on a new lesion.  
- No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional
follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.  
- FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring.  
The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.  
Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.
a phase ii study of
13.4 response criteria 13.4.1 evaluation

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the 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 progressions). 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.
a phase ii study of
13.4.2 evaluation of non-target lesions

Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.  
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).
a phase ii study of
13.4.3 evaluation of best overall

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria  
| For Patients with Measurable Disease (i.e., Target Disease)                                                                                                                                                                                                                                                                                                         |                                                                                    |         |                       |                                                   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|---------|-----------------------|---------------------------------------------------|
| Target                                                                                                                                                                                                                                                                                                                                                              | Non-Target                                                                         | New     | Overall               | Best Overall Response                             |
| Lesions                                                                                                                                                                                                                                                                                                                                                             | Lesions                                                                            | Lesions | Response              | when Confirmation is  Required*                   |
| CR                                                                                                                                                                                                                                                                                                                                                                  | CR                                                                                 | No      | CR                    | >4 wks. Confirmation**                            |
| CR                                                                                                                                                                                                                                                                                                                                                                  | Non-CR/NonPD                                                                                    | No      | PR                    | >4 wks. Confirmation**                            |
| CR                                                                                                                                                                                                                                                                                                                                                                  | Not evaluated                                                                      | No      | PR                    |                                                   |
| PR                                                                                                                                                                                                                                                                                                                                                                  | Non-CR/NonPD/not  evaluated                                                                                    | No      | PR                    |                                                   |
| SD                                                                                                                                                                                                                                                                                                                                                                  | Non-CR/NonPD/not  evaluated                                                                                    | No      | SD                    | Documented at least once  >4 wks. from baseline** |
| PD                                                                                                                                                                                                                                                                                                                                                                  | Any                                                                                | Yes or  | PD                    |                                                   |
| No                                                                                                                                                                                                                                                                                                                                                                  |                                                                                    |         |                       |                                                   |
| Any                                                                                                                                                                                                                                                                                                                                                                 | PD***                                                                              | Yes or  | no prior SD, PR or CR |                                                   |
| PD                                                                                                                                                                                                                                                                                                                                                                  |                                                                                    |         |                       |                                                   |
| No                                                                                                                                                                                                                                                                                                                                                                  |                                                                                    |         |                       |                                                   |
| Any                                                                                                                                                                                                                                                                                                                                                                 | Any                                                                                | Yes     | PD                    |                                                   |
| *                                                                                                                                                                                                                                                                                                                                                                   | See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. |         |                       |                                                   |
| **                                                                                                                                                                                                                                                                                                                                                                  | Only for non-randomized trials with response as primary endpoint.                  |         |                       |                                                   |
| ***                                                                                                                                                                                                                                                                                                                                                                 | In exceptional circumstances, unequivocal progression in non-target lesions may be |         |                       |                                                   |
| accepted as disease progression. Note: Patients with a global deterioration of health status requiring discontinuation of treatment  without objective evidence of disease progression at that time should be reported as "symptomatic  deterioration." Every effort should be made to document the objective progression even after  discontinuation of treatment. |                                                                                    |         |                       |                                                   |  
|                                                                                                                                                                                                                                                | For Patients with Non-Measurable Disease (i.e., Non-Target Disease)   |                  |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------|------------------|
| Non-Target Lesions                                                                                                                                                                                                                             | New Lesions                                                           | Overall Response |
| CR                                                                                                                                                                                                                                             | No                                                                    | CR               |
| Non-CR/non-PD                                                                                                                                                                                                                                  | No                                                                    | Non-CR/non-PD*   |
| Not all evaluated                                                                                                                                                                                                                              | No                                                                    | not evaluated    |
| Unequivocal PD                                                                                                                                                                                                                                 | Yes or No                                                             | PD               |
| Any                                                                                                                                                                                                                                            | Yes                                                                   | PD               |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is  increasingly used as an endpoint for assessment of efficacy in some trials so to assign this  category when no lesions can be measured is not advised |                                                                       |                  |
a phase ii study of
13.4.4 duration of response

Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.  
Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.
a phase ii study of
14.0 data and safety monitoring

In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this trial to review toxicity data. A DSMB will consist of no fewer than 3 members including 2 clinical investigators and a biostatistician. DSMB members must be employed by Washington University, Barnes-Jewish Hospital, or St. Louis Children's Hospital. Like investigators, DSMB members are subject to the Washington University School of Medicine policies regarding standards of conduct. Individuals invited to serve on the DSMB will disclose any potential conflicts of interest to the trial principal investigator and/or appropriate university officials, in accordance with institution policies. Potential conflicts that develop during a trial or a member's tenure on a DSMB must also be disclosed. Until such a time as the first secondary site enrolls its first patient, a semi-annual DSM report to be prepared by the study team will be submitted to the Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually beginning six months after study activation at Washington University (if at least one patient has been enrolled) or one year after study activation (if no patients have been enrolled at the six-month mark). The DSM report for the DSMB will be prepared by the study team with assistance from the study statistician, will be reviewed by the DSMB, and will be submitted to the QASM Committee. The DSMB must meet at least every six months beginning six months after study activation at Washington University or six months after enrollment of the first patient at a secondary site, no more than one month prior to the due date of the DSM report to QASMC. This report will include:
- HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, regulatory coordinator name, and statistician
- Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date of HRPO expiration, date of most recent QA audit, study status, and phase of study
- History of study including summary of substantive amendments; summary of accrual suspensions including start/stop dates and reason; and summary of protocol exceptions, error, or breach of confidentiality including start/stop dates and reason
- Study-wide target accrual and study-wide actual accrual including numbers from participating sites - Protocol activation date at each participating site
- Average rate of accrual observed in year 1, year 2, and subsequent years at each participating site
- Expected accrual end date, accrual by site - Objectives of protocol with supporting data and list the number of participants who have met each objective
- Measures of efficacy - Early stopping rules with supporting data and list the number of participants who have met the early stopping rules
- Summary of toxicities at all participating sites - Abstract submissions/publications - Summary of any recent literature that may affect the safety or ethics of the study Further DSMB responsibilities are described in the DSMB charter. The study principal investigator and Research Patient Coordinator will monitor for serious toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according to institutional guidelines. Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee Policies and Procedures for full details on the responsibilities of the DSMC. This is located on the QASMC website at https://siteman.wustl.edu/research/clinical-research-resources/protocol-office-prmcqasmc/
a phase ii study of
14.1 independent research monitor

Dr. Brian Van Tine, Associate Professor of Medicine and Sarcoma Program Director at Washington University School of Medicine, will serve as the independent research monitor for the trial. The independent research monitor may discuss the research protocol with the investigators, interview human subjects, and consult with others outside of the study about the research. The research monitor shall have authority to stop the research protocol in progress, remove individual human subjects from the research protocol, and take whatever steps are necessary to protect the safety and well-being of human subjects until the IRB can assess the monitor's report. The research monitor has the responsibility to promptly report his/her findings to the IRB or other designated official and to the US Army Medical Research and Materiel Command, Office of Research Protections, Human Research Protection Office. In addition, the independent research monitor is required to review all unanticipated problems involving risk to subjects or others, serious adverse events, and all subject deaths associated with the protocol and provide an unbiased written report of the event. At a minimum, the independent research monitor must comment on the outcomes of the event or problem and in case of a serious adverse event or death, comment on the relationship to participation in the study. The independent research monitor must also indicate whether he/she concurs with the details of the report provided by the principal investigator.
a phase ii study of
15.0 auditing

Since Washington University is the coordinating center, each site will be audited annually by Siteman Cancer Center personnel (QASMC) unless the outside institution has an auditing mechanism in place and can provide a report. The outside sites will be asked to send copies of all audit materials, including source documentation. The audit notification will be sent to the Washington University Research Patient Coordinator, who will obtain the audit materials from the participating institution. Notification of an upcoming audit will be sent to the research team one month ahead of the audit. Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the cases selected for review (up to 10 for each site) will be sent to the research team. However, if during the audit the need arises to review cases not initially selected, the research team will be asked to provide the additional charts within two working days. Additional details regarding the Auditing Policies and procedures can be found at https://siteman.wustl.edu/wp-content/uploads/2015/QASMC-Policies-and-Procedures-03.31.2015.pdf
a phase ii study of
16.0 statistical considerations 16.1 study

1. To determine the clinical benefit (CR+PR+SD>6 months) of neratinib alone in patients with metastatic HER2- breast cancer that carry HER2 mutations (Part I)
2. To examine the clinical benefit (CR+PR+SD>6 months) of neratinib in combination with fulvestrant in patients with fulvestrant naïve metastatic HER2-, ER+ breast cancer carrying activating HER2 mutations (Part II fulvestrant naïve ER+ cohort)
3. To examine the clinical benefit (CR+PR+SD>6 months) of neratinib in combination with fulvestrant in patients with metastatic HER2-, ER+ breast cancer carrying activating HER2 mutations previously treated with fulvestrant (Part II fulvestrant treated ER+ cohort)
4. To determine the clinical benefit rate of neratinib alone in patients with metastatic HER2-, ER- breast cancer carrying activating HER2 mutations (Part II ER- cohort)
a phase ii study of
16.1.2 secondary objectives

1. To determine the PFS of patients treated with neratinib alone in patients with metastatic HER2-, but HER2 mutated breast cancers by ER status and by HER2 mutations (activating vs unknown significance)
2. To assess the PFS and RR of neratinib in combination with fulvestrant in patients with fulvestrant naïve metastatic ER+ HER2- breast cancer carrying activating HER2 mutations 3. To assess the PFS and response rate for neratinib in combination with fulvestrant in patients with metastatic HER2-, ER+ breast cancer carrying activating HER2 mutations previously treated with fulvestrant 4. To correlate the presence of HER2 mutation with histology subtype (invasive lobular vs. invasive ductal cancer), tumor grade (grade 1-2 vs 3), tumor staging at initial diagnosis (I vs. II or III vs. IV), disease free survival in HER2- breast cancer 5. To assess the safety profile and tolerability of neratinib in combination with fulvestrant in patients with metastatic ER+, HER2- breast cancer carrying activating HER2 mutations
a phase ii study of
16.1.3 exploratory objectives

1. To compare the occurrence of HER2 mutation in paired primary and metastatic sites. 2. To collect peripheral blood plasma samples for circulating HER2 mutation analysis. 3. To investigate other potential therapeutic targets in HER2- breast cancer. 4. To explore potential mechanisms of treatment resistance. 5. To explore anti-tumor response of trastuzumab in combination with neratinib alone or neratinib and fulvestrant combination when tumor progresses on single agent neratinib or neratinib and fulvestrant combination, respectively.
a phase ii study of
16.2 study design and sample

Sample size justification for Part I of the study with neratinib alone in metastatic HER2- breast cancer carrying HER2 mutations: Patients with any somatic HER2 mutations identified are eligible for the study. Based on Simon's Optimal 2-stage design, our ultimate goal is to enroll a total of 29 patients with HER2 mutations. This will allow us 80% power at a 1-sided 0.05 significance level to detect an anticipated 20% clinical benefit rate against the null hypothesis of 5%. Ten patients will be enrolled in the first stage. Accrual will continue until 10 patients are considered evaluable for clinical benefit, at which time a decision will be made whether to continue enrollment to the 2nd stage. If none of the 10 patients in the first stage had clinical benefit, we will continue the trial until we enroll 10 patients with known activating mutations by preclinical studies. If 1 or more of the 10 patients in the first stage have shown clinical benefit, a total of 19 patients (with or without known activating mutations, depending on the enrollment criterion in stage 1) will be enrolled in the 2nd stage. In a multicenter study such as this, however, it is difficult for a trial to reach the planned sample exactly. The investigators would not turn away patients who have already been approached for participation just because the number of patients needed has been met. Therefore, we adopted a flexible Phase II design (Chen and Ng 1998) to allow the actual number at final stage to deviate slightly from what is planned. That is, if 4 or more cases with clinical benefit are observed out of 29-34 patients, or 5 or more cases with clinical benefit are observed out of 35 or more patients, we would conclude that preliminary evidence for efficacy exists and that further investigation of the treatment is warranted.  
As of Jan 17th 2015, 10 evaluable patients with HER2 mutations, including 9 with activating mutations, were enrolled in the study. Among these patients, 1 patient with activating mutation derived clinical benefit with a partial response. However, since majority of patients (15 of 16) found to have HER2 mutations in the study had ER+ breast cancer, we propose to add fulvestrant to neratinib in the ER+ population in the second part of the study to evaluate the overall response rate for this combination. The first part of the trial will close once the amendment (amendment 7)
for the second part of the trial is approved. As of August 25th, 2015, amendment 7 has been approved by all participating institutions; therefore enrollment is only open to the second part trial since that date. Sample size justification for the second part of the trial with neratinib alone in patients with metastatic ER- HER2- breast cancer carrying HER2 mutations: We will enroll 10 patients. This will provide us a reasonable precision to estimate the clinical benefit (CR+PR+SD>6 months) of neratinib alone in patients with metastatic ER-/HER2- breast cancer that carry HER2 mutations. If 2 clinical benefits are observed out of 10 patients, for example, we will have 80% confidence that the true rate will be above 5%. Conversely, if the "true" response rate is above 20%, there will only 10% chance to observe none clinical benefit out of 10 patients. Sample size justification for the Part II fulvestrant naïve ER+ Cohort: Based on the phase III trials PALOMA 3 (fulvestrant alone vs fulvestrant + palbo), the CBR for fulvestrant naïve endocrine resistant population is 40% and adding palbo increase CBR to 67%. We propose a sample size of 26 evaluable patients. Based on Simon's Minimax design, this will allow us 80% power at a 1sided 0.05 significance level to detect an anticipated 65% response rate for fulvestrant plus neratinib combination therapy against the null hypothesis of 40%. Specifically, 12 patients will be enrolled in the first stage. If 6 or more clinical benefits are observed out of these 12 patients, additional 14 patients will be enrolled to the 2nd-stage. If 15 or more cases with clinical benefits are observed out of 26 patients, we would conclude that preliminary evidence for efficacy exists and that further investigation of the treatment is warranted. If the "true" response rate is 40% or less, this design allows us 67% chance to stop the trial earlier. Sample size justification for the Part II fulvestrant treated ER+ Cohort: Patients enrolled in this cohort has had disease progression on prior fulvestrant, therefore we anticipate fulvestrant alone would be ineffective. Since neratinib alone resulted in clinical benefit rate of 38.5% (5 of 13 evaluable patients with metastatic ER+ breast cancer that carry activating HER2 mutations) based on the preliminary efficacy data observed in the part I of this trial, we propose a sample size of 41 evaluable patients. Based on Simon's Minimax design, this will allow us 80% power at a 1-sided 0.05 significance level to detect an anticipated 55% clinical benefit rate for fulvestrant plus neratinib combination therapy against the null hypothesis of 35%. Specifically, 21 patients will be enrolled in the first stage. If 9 or more clinical benefits are observed out of 21 patients, additional 20 patients will be enrolled to the 2nd-stage. If 20 or more cases with clinical benefit are observed out of 41 patients, we would conclude that preliminary evidence for efficacy exists and that further investigation of the treatment is warranted. If the "true" benefit rate is 35% or less, this design allows us 70% chance to stop the trial earlier. In total, 77 patients (10 ER-, 26 ER+ fulvestrant naïve, 41 ER+ fulvestrant treated) will be
a phase ii study of
enrolled in part ii of

Data analysis will be performed for Parts I and II separately. Only patients with tumors tested positive for HER2 mutations are eligible for study therapy but the clinical and pathology data will be collected for all screened patients. Subset analysis will also be performed on patients with known activating mutations if needed. For patients with HER2 mutation, the number and percentage of responses to neratinib alone (Part I, and Part II ER- cohort) or neratinib in combination with fulvestrant (Part II, fulvestrant naïve and fulvestrant treated cohorts) will be tabulated. The rate of overall clinical benefit (CR, PR, or SD > 6 months) and its 90% confidence interval (CI) will be calculated in each cohort separately. The time to progression or death will be listed, and the progression-free survival (PFS) will be estimated using Kaplan-Meier product limit method in each cohort. For all the enrolled patients, the number and percentage of patients with HER2 mutation will be presented, and its 95% CI will also be calculated. The agreement for the occurrence of HER2 mutation in paired primary and metastatic sites will be described using contingency tables and assess by McNemar test. The association of the presence of HER2 mutation with histology subtype (invasive lobular vs invasive ductal cancer), tumor grade, tumor staging at initial diagnosis (I vs II or III vs IV), and diseasefree survival (DFS) will be assessed using Fisher's exact test, Mann-Whitney rank sum test, or log-rank test as appropriate.
a phase ii study of
17.0 multicenter regulatory requirements

Washington University requires that each participating site sends its informed consent document to be reviewed and approved by the Washington University Principal Investigator (or designee) prior to IRB/IEC submission. Each participating institution must have the following documents on file at Washington University prior to first subject enrollment:
- Documentation of IRB approval of the study in the form of a letter or other official document from the participating institution's IRB. This documentation must show which version of the protocol was approved by the IRB.  
- Documentation of IRB approval of an informed consent form. The consent must include a statement that data will be shared with Washington University, including the Quality Assurance and Safety Monitoring Committee (QASMC), the DSMC (if applicable), and the Washington University study team.  
- Documentation of FWA, signed FDA Form 1572, and signed and dated CVs of all participating investigators.  
- Documentation of training in protection of human subjects by all participating investigators.  
- Protocol signature page signed and dated by the investigator at each participating site.  
The Principal Investigator is responsible for disseminating to the participating sites all study updates, amendments, reportable adverse events, etc. There will be one current version of the protocol document at any given time and each participating institution will utilize that document. Protocol/consent modifications and IB updates will be forwarded electronically to the secondary sites within 2 weeks of obtaining Washington University IRB approval with acknowledgement of receipt requested. Secondary sites are to submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt, and confirmation of submission must be forwarded to the appropriate contact person on the Washington University study team at the time of submission. Upon the secondary sites obtaining local IRB approval, documentation of such shall be sent to the Washington University study team within 2 weeks of receipt of approval. Documentation of participating sites' IRB approval of annual continuing reviews, protocol amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must be kept on file at Washington University. The investigator or a designee from each institution must participate in a regular conference call to update and inform regarding the progress of the trial.
a phase ii study of
18.0 references

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Miller N, Woolfrey JR *et al*: EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation. Clinical cancer research : an official journal of the American Association for Cancer Research 2008, 14(8):2465-2475.  
60. Kancha RK, von Bubnoff N, Bartosch N, Peschel C, Engh RA, Duyster J: Differential sensitivity of ERBB2 kinase domain mutations towards **lapatinib**. *PloS one* 2011, 6(10):e26760.  
61. Rexer BN, Ghosh R, Narasanna A, Estrada MV, Chakrabarty A, Song Y, Engelman JA, Arteaga CL: Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2. Clinical cancer research : an official journal of the American Association for Cancer Research 2013, 19(19):5390-5401.  
62. Sun Z, Shi Y, Shen Y, Cao L, Zhang W, Guan X: Analysis of different HER‐**2 mutations in**
breast cancer **progression and drug resistance**. *Journal of Cellular and Molecular Medicine* 2015, 19(12):2691-2701.  
63. Gilmer TM, Cable L, Alligood K, Rusnak D, Spehar G, Gallagher KT, Woldu E, Carter HL,
Truesdale AT, Shewchuk L *et al*: Impact of common epidermal growth **factor receptor and** HER2 variants on receptor activity and inhibition by lapatinib. *Cancer research* 2008, 68(2):571-579.  
64. Hu Z, Hu Y, Liu X, Xi R, Zhang A, Liu D, Xie Q, Chen L: **Tumor driven by gain-of-function**
HER2 H878Y mutant is highly sensitive to HER2 inhibitor. *Oncotarget* 2015, 6(31):3162831639.  
65. Fan YX, Wong L, Ding J, Spiridonov NA, Johnson RC, Johnson GR: Mutational activation of ErbB2 reveals a new protein kinase autoinhibition mechanism. *J Biol Chem* 2008, 283(3):1588-1596.  
66. Minami Y, Shimamura T, Shah K, LaFramboise T, Glatt KA, Liniker E, Borgman CL,
Haringsma HJ, Feng W, Weir BA *et al*: **The major lung cancer-derived mutants of ERBB2** are oncogenic and are associated with sensitivity to the irreversible EGFR//ERBB2 inhibitor HKI-272. *Oncogene* 2007, 26(34):5023-5027.  
67. Wang SE, Narasanna A, Perez-Torres M, Xiang B, Wu FY, Yang S, Carpenter G, Gazdar AF,
Muthuswamy SK, Arteaga CL: HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. *Cancer Cell* 2006, 10(1):25-38.  
68. Ma CX, Bose R, Gao F, Freedman RA, Telli ML, Kimmick G, Winer EP, Naughton MJ, Goetz MP, Russell C *et al*: Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Non-amplified Metastatic Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2017.  
69. De Mattos-Arruda L, Caldas C: **Cell-free circulating tumour DNA as a liquid biopsy in**
breast cancer. Mol *Oncol* 2016, 10(3):464-474.  
70. Lanman RB, Mortimer SA, Zill OA, Sebisanovic D, Lopez R, Blau S, Collisson EA, Divers SG,
Hoon DS, Kopetz ES *et al*: **Analytical and Clinical Validation of a Digital Sequencing Panel**
for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA. *PloS*
one 2015, 10(10):e0140712.  
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core which provided protocol development, study coordination, and regulatory coordination services. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant \#P30 CA91842.  
| Grade   | Description                                                                                                                                                                                     |
|---------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0       | Normal activity. Fully active, able to carry on all pre-disease  performance without restriction. Symptoms, but ambulatory. Restricted in physically strenuous                                  |
| 1       | activity, but ambulatory and able to carry out work of a light or  sedentary nature (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, but |
| 2       | unable to carry out any work activities. Up and about more than 50%  of waking hours.                                                                                                           |
| 3       | In bed >50% of the time. Capable of only limited self-care, confined  to bed or chair more than 50% of waking hours.                                                                            |
| 4       | 100% bedridden. Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair.                                                                                          |
| 5       | Dead.                                                                                                                                                                                           |
appendix a ecog performance status
18.0 references

Cycle: Patient Name:
1. Complete one form for each month. Take _____mg ( ___tablets) of neratinib daily with food every morning.  
2. Record the date, the number of capsules taken, and when you took them.  
3. If you forget to take your neratinib dose within 12 hours of the usual time, do not take a dose that day.  
Restart taking the neratinib the next day.  
4. If you have any questions or notice any side effects, please record them in the comments section.  
Record the time if you should vomit.  
5. Please return the forms to your physician or your study coordinator when you go to your next appointment. Please bring your unused study medications and/or empty bottles with you to each clinic visit so that a pill count can be done.  
6. Avoid St. John's wort, grapefruit, grapefruit juice, grapefruit hybrids, and star fruit from 7 days before you start taking neratinib and throughout the entire study.  
Day Date What time was dose taken?  
\# of tablets taken
\# of loose stools Antidiarrheals taken? y/n Comments  
| visit so that a pill count can be done.                                    |                                                                                                                                                                         |               |              |            |                |          |
|----------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|--------------|------------|----------------|----------|
| 6.                                                                         | Avoid St. John's wort, grapefruit, grapefruit juice, grapefruit hybrids, and star fruit from 7 days before you  start taking neratinib and throughout the entire study. |               |              |            |                |          |
| Day                                                                        | Date                                                                                                                                                                    | What time was | # of tablets | # of loose | Antidiarrheals | Comments |
| dose taken?                                                                | taken                                                                                                                                                                   | stools        | taken? y/n   |            |                |          |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 |                                                                                                                                                                         |               |              |            |                |          |
appendix c patient instructions for
18.0 references

Please review these instructions with your study doctor/team. Once all of your questions are answered, sign at the bottom and make sure you are given a copy of these instructions to take home.  
Diarrhea is the most common side effect you may have while participating in this study. Diarrhea usually starts within a few hours to a few days of the first dose of study drug. In order to reduce or even prevent diarrhea as far as possible, you will be supplied with an anti-diarrheal medicine called loperamide to take at the start of the study. Primary prophylactic use of antidiarrheal medication is mandatory for all enrolled subjects. Loperamide will be dispensed directly by your study doctor/team on day 1 with the instruction to initiate treatment with loperamide at the same time as you take your first dose of neratinib. Start taking the anti-diarrheal medication immediately with the first dose of neratinib as directed by your study doctor/team. Your study doctor/team will call you 1 day, 2 days and 3 days after your first dose of study drug to find out if you are experiencing diarrhea and to provide further treatment instructions and advice if necessary. You will also have an easy to follow flow-chart to help you each day in the management of diarrhea if it is present. If you are having new-onset diarrhea, persistent diarrhea or diarrhea with increase of 7 or more stools per day over usual, call your study doctor/team at 314-362-8903 to let them know so they can work with you to control the diarrhea. If you are dizzy or weak because of diarrhea, go to the study doctor's office or go to the hospital immediately. Please record the number of stools and any anti-diarrheal treatment during the first two cycles along with the daily dose of study medication in your diary and return the completed diary at the next scheduled visit.
appendix c patient instructions for
information to provide when talking

When talking to the study doctor/team I will provide as much of the information below as possible, in order to help my study doctor/team to assess my diarrhea and decide on the best treatment:
- Number of stools per day as compared to my normal bowel habits
- Presence of diarrhea during the night - Presence of fever, dizziness, abdominal pain/cramping, or weakness
- What the stool looks like, that is, watery stools, blood, or mucus
- When I took my last study drug - Any other information that could explain my diarrhea (food, recent travel, contact with other people with diarrhea).  
Medications to treat diarrhea My study doctor/team will provide me with loperamide on day 1 with the instruction to start treatment with loperamide along with the first dose of neratinib. I need to take the medications as directed by my study doctor/team.  
Loperamide:
- I will take 2 tablets/capsules (4 mg) with the first dose of neratinib
- After the first dose, I will take 4 mg (2 tablets/ capsules) three times daily for the first 14 days(not to exceed a total of 8 tablets/day; if I get constipated, I should contact my study doctor/team who will instruct me on how often and how much loperamide to take but I should not stop taking loperamide).  
- After the first 14 days, I will take 2 tablets (4 mg) two times per day until the end of the second cycle of therapy regardless of whether I have diarrhea or not. If I get constipated, I should contact my study doctor/team who will instruct me on how often and how much loperamide to take but I should not stop taking loperamide).  
- If I continue to have diarrhea while taking loperamide, I should contact my study doctor/team for additional anti-diarrheal medication.  
- If I have diarrhea with increase of up to 6 stools per day over usual any time after completing the second cycle of therapy and I am not taking any anti-diarrheal medication, I will take 4mg (2 tablets/capsules) as needed (not to exceed 8 tablets capsules or 16 mg per day)
- □ Other medication (Study doctor/team to write in name of medication and instructions):
________________________________________________________
______________________________________________________________________ ______________________________________________________________________
In case of more severe diarrhea and any diarrhea associated with fever, pain, infection, or dehydration, I may receive IV fluids, antibiotics and/or other medications.  
Changes to my diet to treat diarrhea If I have diarrhea, I will:
- Stop all lactose-containing products (milk, yogurt, cheese, etc)
- Drink 8 to 10 large glasses of clear liquids per day - Eat frequent small meals
- Eat low fat foods such as the BRAT diet that includes bananas, rice, applesauce, and/or toast:
- The BRAT diet is a bland diet that is low in fat and fiber and will not irritate the stomach; - Bananas are high in potassium and can cause constipation which can help alleviate the diarrhea
- Other similar foods are crackers, cooked cereals and pasta - This diet is not complete in nutrients and should only be taken for a short period of time and only upon the doctor's advice
My study doctor/team may have other suggestions for me. (Study doctor/team to write in any suggestions). ________________________________________________________
appendix c patient instructions for
study medication adjustments

If I am experiencing loose stools or diarrhea and cannot reach my study doctor/team immediately, I will start taking anti-diarrheal medication per the instructions above until further advice is given by my study doctor/team. If I have more than 4-6 stools per day compared to normal despite taking anti-diarrheal medication for 24 hours, I will stop taking the study medication and wait for further instructions from my study doctor/team. My signature below indicates I have reviewed this information and have received the following medications: □ Neratinib Tablets
□ Loperamide
________________________________________________________________ Study participant name Study participant Signature and Date ________________________________________________________________ Investigator delegate name Investigator delegate Signature and Date OR ________________________________________________________________ Investigator name Investigator Signature and Date Do you have diarrhea?  
  
APPENDIX D: RECIST 1.1 Tumor Evaluation Form  
Patient Name DOB Study PI Page 1  
Please record the following: * Description of Target, Non-Target, or New Lesions * Maximum of 5 Target lesions Version Date 10/30/2012  
* Dimensional measurements of Lymph Nodes *(LNs)* are *shortest* axis and >1.5 cm * All other lesions are *longest* axis.  
* Follow Up Status of Non-Target Lesions: Increase/Decrease/Stable/Resolved  
Date of Evaluation  
Target Lesions *Baseline*  
| Date of Evaluation Target Lesions            | Baseline   | Dimension cm          |         |            |          |         |            |          |         |
|----------------------------------------------|------------|----------|---------|------------|----------|---------|------------|----------|---------|
| #1                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #2                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #3                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #4                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #5                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| 0.0                                          | 0.0        | 0.0      | 0.0     |            |          |         |            |          |         |
| Image #                                      | Dimension cm            | Modality | Image # | Dimension cm            | Modality | Image # | Dimension cm            | Modality | Image # |
| Site #/Description                           | Modality   |          |         |            |          |         |            |          |         |
| Sum of Longest Dimensions Non-Target Lesions | F/U Status |          |         |            |          |         |            |          |         |
| #1                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #2                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #3                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #4                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #5                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #6                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #7                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #8                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| Image #                                      | F/U Status | Modality | Image # | F/U Status | Modality | Image # | F/U Status | Modality | Image # |
| Site #/Description                           | Modality   |          |         |            |          |         |            |          |         |
| New Lesions                                  | Dimension cm            |          |         |            |          |         |            |          |         |
| #1                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #2                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #3                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #4                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| #5                                           | CT         | CT       | CT      | CT         |          |         |            |          |         |
| Image #                                      | Dimension cm            | Modality | Image # | Dimension cm            | Modality | Image # | Dimension cm            | Modality | Image # |
| Site #/Description                           | Modality   |          |         |            |          |         |            |          |         |
| Comments                                     |            |          |         |            |          |         |            |          |         |  
Initials/Date of Form Prep/Data Entry *SignatureDate* Official IRAC Document - Do Not Modify - IRAC Staff Use Only
appendix c patient instructions for
appendix e definitions adverse events

Definition: any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. Grading: the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for all toxicity reporting. A copy of the CTCAE version 4.03 can be downloaded from the CTEP website. Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms listed that should be used are those provided by the Department of Health and Human Services' Office for Human Research Protections (OHRP). A copy of this guidance can be found on OHRP's website: http://www.hhs.gov/ohrp/policy/advevntguid.html
appendix c patient instructions for
suspected adverse reaction (sar)

Definition: any adverse event for which there is a reasonable possibility that the drug caused the adverse event. "Reasonable possibility" means there is evidence to suggest a causal relationship between the drug and the adverse event. "Suspected adverse reaction" implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug
appendix c patient instructions for
serious adverse event (sae) or

As defined in 21 CFR 312.32  
Definition: an adverse event or suspected adverse reaction is considered "serious" if, in the view of the investigator, it results in any of the following outcomes:
o Death o A life-threatening adverse event o Inpatient hospitalization or prolongation of existing hospitalization o A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions o A congenital anomaly/birth defect o Any other important medical event that does not fit the criteria above but, based upon appropriate medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above
appendix c patient instructions for
unexpected adverse experience

Definition: any adverse drug experience, the specificity or severity of which is not consistent with the current investigator brochure (or risk information, if an IB is not required or available). Events that are both serious AND unexpected where there is a reasonable possibility of relationship to study drug must be reported to the FDA.
appendix c patient instructions for
life-threatening adverse event / life

Definition: any adverse drug event or suspected adverse reaction is considered "life-threatening" if, in the view of the investigator, its occurrence places the patient at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death.
appendix c patient instructions for
unanticipated problems definition

- unexpected (in terms of nature, severity, or frequency based on the adverse reaction table (Table 63) in the most current Investigator Brochure) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;
- related or possibly related to participation in the research (in this guidance document, possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
- suggests that the research places subjects or others at a greater risk of harm
(including physical, psychological, economic, or social harm) than was previously known or recognized.
appendix c patient instructions for
noncompliance

Definition: failure to follow any applicable regulation or institutional policies that govern human subjects research or failure to follow the determinations of the IRB. Noncompliance may occur due to lack of knowledge or due to deliberate choice to ignore regulations, institutional policies, or determinations of the IRB.
appendix c patient instructions for
serious noncompliance

Definition: noncompliance that materially increases risks, that results in substantial harm to subjects or others, or that materially compromises the rights or welfare of participants.
appendix c patient instructions for
protocol exceptions

Definition: A planned deviation from the approved protocol that are under the research team's control. Exceptions apply only to a single participant or a singular situation. Local IRB pre-approval of all protocol exceptions must be obtained prior to the event. For secondary sites, the Washington University PI will issue approval of the exception, but it must also be submitted to the local IRB with documentation of approval forwarded to Washington University. Washington University IRB approval is not required for protocol exceptions occurring at secondary sites.  
| APPENDIX F: Reporting Timelines                                                                                           | Expedited Reporting Timelines                                                                                                               |                                            |     |     |                     |
|---------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|-----|-----|---------------------|
| Event                                                                                                                     | HRPO                                                                                                                                        | QASMC                                      | FDA | IBC | Puma Biotechnology, |
| (Not Applicable)                                                                                                          | Inc.                                                                                                                                        |                                            |     |     |                     |
| Serious AND  unexpected suspected  adverse reaction                                                                       | Report no later than 15  calendar days after it is  determined that the  information qualifies for  reporting                               | Report within fifteen (15)  days           |     |     |                     |
| Unexpected fatal or  life-threatening  suspected adverse  reaction                                                        | Report no later than 7  calendar days after initial  receipt of the information                                                             | Report within seven (7)  days              |     |     |                     |
| Unanticipated  problem involving risk  to participants or  others                                                         | Report within 10 working days.  If the event results in the death  of a participant enrolled at  WU/BJH/SLCH, report within  1 working day. | Report via email after  IRB acknowledgment |     |     |                     |
| Major deviation                                                                                                           | Report within 10 working days.  If the event results in the death  of a participant enrolled at  WU/BJH/SLCH, report within  1 working day. |                                            |     |     |                     |
| A series of minor  deviations that are  being reported as a  continuing  noncompliance                                    | Report within 10 working days.                                                                                                              |                                            |     |     |                     |
| Protocol exception                                                                                                        | Approval must be obtained  prior to implementing the  change                                                                                |                                            |     |     |                     |
| Clinically important  increase in the rate of  a serious suspected  adverse reaction of  that list in the protocol  or IB | Report no later than 15  calendar days after it is  determined that the  information qualifies for  reporting                               |                                            |     |     |                     |
| Complaints                                                                                                                | If the complaint reveals an  unanticipated problem  involving risks to participants  or others OR noncompliance,                            |                                            |     |     |                     |  
Page 84  
| Expedited Reporting Timelines                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                 |                                                                                                                    |                                                                                                              |                                                                                            |                     |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------|---------------------|
| Event                                                                                                                                                                                             | HRPO                                                                                                                                                                                                                                                                                                            | QASMC                                                                                                              | FDA                                                                                                          | IBC                                                                                        | Puma Biotechnology, |
| (Not Applicable)                                                                                                                                                                                  | Inc.                                                                                                                                                                                                                                                                                                            |                                                                                                                    |                                                                                                              |                                                                                            |                     |
| report within 10 working days.  If the event results in the death  of a participant enrolled at  WU/BJH/SLCH, report within  1 working day. Otherwise,  report at the time of continuing  review. |                                                                                                                                                                                                                                                                                                                 |                                                                                                                    |                                                                                                              |                                                                                            |                     |
| Breach of                                                                                                                                                                                         | Within 10 working days.                                                                                                                                                                                                                                                                                         |                                                                                                                    |                                                                                                              |                                                                                            |                     |
| confidentiality Incarceration                                                                                                                                                                     | If withdrawing the participant  poses a safety issue, report  within 10 working days.  If withdrawing the participant  does not represent a safety issue  and the patient will be  withdrawn, report at continuing  review.                                                                                     | Routine Reporting Timelines                                                                                        |                                                                                                              |                                                                                            |                     |
| Event                                                                                                                                                                                             | HRPO                                                                                                                                                                                                                                                                                                            | QASMC                                                                                                              | FDA                                                                                                          | Puma Biotechnology, Inc.                                                                   |                     |
| Adverse event or SAE  that does not require  expedited reporting                                                                                                                                  | If they do not meet the definition of an  unanticipated problem involving risks to  participants or others, report summary  information at the time of continuing review                                                                                                                                        | Adverse events will be  reported in the toxicity  table in the DSM report  which is typically due  every 6 months. | The most current  toxicity table from the  DSM report is provided  to the FDA with the  IND's annual report. | Report within thirty (30) days (i.e., unrelated to study  drugs or listed/expected  event) |                     |
| Minor deviation                                                                                                                                                                                   | Report summary information at the time of  continuing review.                                                                                                                                                                                                                                                   |                                                                                                                    |                                                                                                              |                                                                                            |                     |
| Complaints                                                                                                                                                                                        | If the complaint reveals an unanticipated problem  involving risks to participants or others OR  noncompliance, report within 10 working days. If  the event results in the death of a participant  enrolled at WU/BJH/SLCH, report within 1  working day. Otherwise, report at the time of  continuing review. |                                                                                                                    |                                                                                                              |                                                                                            |                     |
| Incarceration                                                                                                                                                                                     | If withdrawing the participant poses a safety  issue, report within 10 working days.                                                                                                                                                                                                                            |                                                                                                                    |                                                                                                              |                                                                                            |                     |  
Page 85  
| Routine Reporting Timelines                                                                                                                                                          |                                                                                 |                                                                                           |                                                                                                                         |                                                                                                                                 |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------|
| If withdrawing the participant does not represent a  safety issue and the patient will be withdrawn,  report at continuing review. Expedited Reporting Timelines for Secondary Sites |                                                                                 |                                                                                           |                                                                                                                         |                                                                                                                                 |
| Event                                                                                                                                                                                | WU (Coordinating Center)                                                        | Local IRB                                                                                 | FDA                                                                                                                     | Puma Biotechnology, Inc.                                                                                                        |
| Serious AND unexpected                                                                                                                                                               | Report no later than 11 calendar days                                           |                                                                                           |                                                                                                                         |                                                                                                                                 |
| suspected adverse reaction                                                                                                                                                           | after it is determined that the information  qualifies for reporting.           | Report all applicable  events to local IRB  according to local  institutional guidelines. | The research team at  Washington University is  responsible for reporting all  applicable events to the  FDA as needed. | The research team at  Washington University is  responsible for reporting all  applicable events to  [MANUFACTURER] as  needed. |
| Unexpected fatal or lifethreatening suspected  adverse reaction                                                                                                                                                                                      | Report no later than 4 calendar days after  initial receipt of the information. |                                                                                           |                                                                                                                         |                                                                                                                                 |
| Unanticipated problem  involving risk to participants  or others                                                                                                                     | Report no later than 4 calendar days after  initial receipt of the information. |                                                                                           |                                                                                                                         |                                                                                                                                 |
| Adverse event or SAE that  does not require expedited  reporting                                                                                                                     | As per routine data entry expectations                                          |                                                                                           |                                                                                                                         |                                                                                                                                 |
| Protocol exception                                                                                                                                                                   | Approval must be obtained prior to  implementing the change.                    |                                                                                           |                                                                                                                         |                                                                                                                                 |  
APPENDIX G: Washington University Serious Adverse Event Reporting Cover Sheet  
| Washington University HRPO#:   | Sponsor-Investigator:              |
|--------------------------------|------------------------------------|
| Subject Initials:              | Subject ID:                        |
| Treating MD:                   | Treating Site:                     |
| EVENT TERM:                    | Event Start Date:                  |
| EVENT GRADE:                   | Date of site's first notification: |  
SAE COVER SHEET- **Secondary Site Assessment**
Treating MD Event Assessment: Is this event **possibly, probably, or definitely** related study treatment?  
yes no If yes, please list which drug (if more than one)______________________________ Explain ______________________________________________________________________ _________________________ ___________________________ _________________ Physician's Name Physician's Signature Date