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13.1 arm 1 ddac thp

| End of  Study (Adjuvant  anti-Her2  therapy  and  endocrine  therapy as  per  protocol)   | Follow-up           |         |         |         |                               |         |         |                                                              |
|-------------------------------------------------------------------------------------------|---------------------|---------|---------|---------|-------------------------------|---------|---------|--------------------------------------------------------------|
|                                                                                           | Screening           | Cycle 1 | Cycle 2 | Cycle 3 | Cycle 4                       | Cycle 5 | Surgery | Q 3 months  for first year  and q 6  months for  second year |
| Medication Administration Visit Day                                                       | Day                 | Day     | Day     | Day     | Day 1, 8, 15, 22, 29, 36, 43, |         |         |                                                              |
| Day 1                                                                                     | 2                   | Day 1   | 2       | Day 1   | 2                             | Day 1   | 2       | 50, 57, 64, 71, 78                                           |
| Doxorubicin                                                                               | X                   | X       | X       | X       |                               |         |         |                                                              |
| Cyclophosphamide                                                                          | X                   | X       | X       | X       |                               |         |         |                                                              |
| Pegfilgastrim                                                                             | X                   | X       | X       | X       |                               |         |         |                                                              |
| Paclitaxel                                                                                | X                   |         |         |         |                               |         |         |                                                              |
| Trastuzumab                                                                               | X (day 1,22,43, 64) |         |         |         |                               |         |         |                                                              |
| Pertuzumab                                                                                | X(day 1,22,43, 64)  |         |         |         |                               |         |         |                                                              |
| LABS                                                                                      | X                   | X       | X       | X       |                               |         |         |                                                              |
| cbc                                                                                       | X (SOC)             | (SOC)   | (SOC)   | (SOC)   | (SOC)                         | X (SOC) |         |                                                              |
| Comprehensive                                                                             | X                   | X       | X       | X       |                               |         |         |                                                              |
| panel                                                                                     | X (SOC)             | (SOC)   | (SOC)   | (SOC)   | (SOC)                         | X (SOC) |         |                                                              |
| Imaging Staging: CT C/A/P  and bone scan or                                               |                     |         |         |         |                               |         |         |                                                              |
| PET scan                                                                                  | X (SOC)             |         |         |         |                               |         |         |                                                              |  
| Echo (q 3 months)                                            | X (SOC)       | X (Around Day 29) (SOC)   | X (for 1st year)   |       |       |         |         |
|--------------------------------------------------------------|---------------|---------------------------|--------------------|-------|-------|---------|---------|
| Echo annually                                                | X For 2 years |                           |                    |       |       |         |         |
| Pathology Assessments Pre -chemotherapy  biopsy, Her2 status |               |                           |                    |       |       |         |         |
| confirmed                                                    | X (SOC)       |                           |                    |       |       |         |         |
| Assessment of pCR                                            |               |                           |                    |       |       |         |         |
| by pathologists                                              | X (SOC)       |                           |                    |       |       |         |         |
| Visit Assessments Informed consent                           | X             |                           |                    |       |       |         |         |
| Inclusion/Exclusion                                          |               |                           |                    |       |       |         |         |
| Criteria                                                     | X             |                           |                    |       |       |         |         |
| Demographics                                                 | X (SOC)       | X (SOC)                   |                    |       |       |         |         |
| Medical history                                              | X (SOC)       | X (SOC)                   |                    |       |       |         |         |
| Concurrent meds                                              | X (SOC)       | X (SOC)                   |                    |       |       |         |         |
| History and                                                  | X             | X                         | X                  | X     |       |         |         |
| Physical exam                                                | X (SOC)       | (SOC)                     | (SOC)              | (SOC) | (SOC) | X (SOC) | X (SOC) |
| X                                                            | X             | X                         | X                  |       |       |         |         |
| Vital signs                                                  | X (SOC)       | (SOC)                     | (SOC)              | (SOC) | (SOC) | X (SOC) | X (SOC) |
| X                                                            | X             | X                         | X                  |       |       |         |         |
| Height                                                       | X (SOC)       | (SOC)                     | (SOC)              | (SOC) | (SOC) | X (SOC) | X (SOC) |
| X                                                            | X             | X                         | X                  |       |       |         |         |
| Weight                                                       | X (SOC)       | (SOC)                     | (SOC)              | (SOC) | (SOC) | X (SOC) | X (SOC) |
| X                                                            | X             | X                         | X                  |       |       |         |         |
| BSA                                                          | X (SOC)       | (SOC)                     | (SOC)              | (SOC) | (SOC) | X (SOC) | X (SOC) |
| Performance                                                  | X             | X                         | X                  | X     |       |         |         |
| status                                                       | X (SOC)       | (SOC)                     | (SOC)              | (SOC) | (SOC) | X (SOC) | X (SOC) |
| Adverse event                                                |               |                           |                    |       |       |         |         |
| evaluation                                                   | X             | X                         | X                  | X     | X     | X       |         |
| Study Assessments                                            |               |                           |                    |       |       |         |         |  
| X  (time  "0")   | X   | X   | X (Day 29)   |
|------------------|-----|-----|--------------|
| Troponin I       | X   |     |              |  
13.2 Arm 2: TCHP  
|                                                      | Pre     | End of   |         |         |         |         |         |       |                                                                         |       |    |
|------------------------------------------------------|---------|----------|---------|---------|---------|---------|---------|-------|-------------------------------------------------------------------------|-------|----|
| Study                                                | Cycle 1 | Cycle 2  | Cycle 3 | Cycle 4 | Cycle 5 | Cycle 6 | Surgery | Study | Follow-up  Q 3 months  for first year  and q 6  months for  second year |       |    |
| Visit Day                                            | Day     | Day      | Day     | Day     | Day     | Day     |         |       |                                                                         |       |    |
| Day 1                                                | 2       | Day 1    | 2       | Day 1   | 2       | Day 1   | 2       | Day 1 | 2                                                                       | Day 1 | 2  |
| Medication Administration Docetaxel                  | X       | X        | X       | X       | X       | X       |         |       |                                                                         |       |    |
| Carboplatin                                          | X       | X        | X       | X       | X       | X       |         |       |                                                                         |       |    |
| Trastuzumab                                          | X       | X        | X       | X       | X       | X       |         |       |                                                                         |       |    |
| Pertuzumab                                           | X       | X        | X       | X       | X       | X       |         |       |                                                                         |       |    |
| Pegfilgastrim                                        | X       | X        | X       | X       | X       | X       |         |       |                                                                         |       |    |
| Labs                                                 | X       | X        | X       | X       | X       | X       |         |       |                                                                         |       |    |
| cbc                                                  | X (SOC) | (SOC)    | (SOC)   | (SOC)   | (SOC)   | (SOC)   | (SOC)   |       |                                                                         |       |    |
| X                                                    | X       | X        | X       | X       | X       |         |         |       |                                                                         |       |    |
| Comprehensive panel                                  | X (SOC) | (SOC)    | (SOC)   | (SOC)   | (SOC)   | (SOC)   | (SOC)   |       |                                                                         |       |    |
| Imaging Staging: CT C/A/P and  bone scan or PET scan | X (SOC) |          |         |         |         |         |         |       |                                                                         |       |    |  
| X                                                                       |             |         |                  |       |       |       |       |         |
|-------------------------------------------------------------------------|-------------|---------|------------------|-------|-------|-------|-------|---------|
| Echo (q 3 months)                                                       | X (SOC)     | (SOC)   | X (for 1st year) |       |       |       |       |         |
| Echo annually                                                           | For 2 years |         |                  |       |       |       |       |         |
| Pathology Assessments Pre -chemotherapy  biopsy, Her2 status  confirmed | X (SOC)     |         |                  |       |       |       |       |         |
| Assessment of pCR by  pathologists                                      | X (SOC)     |         |                  |       |       |       |       |         |
| Visit Assessments Informed consent                                      | X           |         |                  |       |       |       |       |         |
| Inclusion/Exclusion  Criteria                                           | X           |         |                  |       |       |       |       |         |
| Demographics                                                            | X (SOC)     | X (SOC) |                  |       |       |       |       |         |
| Medical history                                                         | X (SOC)     | X (SOC) |                  |       |       |       |       |         |
| Concurrent meds                                                         | X (SOC)     | X (SOC) |                  |       |       |       |       |         |
| History and Physical                                                    | X           | X       | X                | X     | X     | X     |       |         |
| exam                                                                    | X (SOC)     | (SOC)   | (SOC)            | (SOC) | (SOC) | (SOC) | (SOC) | X (SOC) |
| X                                                                       | X           | X       | X                | X     | X     |       |       |         |
| Vital signs                                                             | X (SOC)     | (SOC)   | (SOC)            | (SOC) | (SOC) | (SOC) | (SOC) | X (SOC) |
| X                                                                       | X           | X       | X                | X     | X     |       |       |         |
| Height                                                                  | X (SOC)     | (SOC)   | (SOC)            | (SOC) | (SOC) | (SOC) | (SOC) | X (SOC) |
| X                                                                       | X           | X       | X                | X     | X     |       |       |         |
| Weight                                                                  | X (SOC)     | (SOC)   | (SOC)            | (SOC) | (SOC) | (SOC) | (SOC) | X (SOC) |
| X                                                                       | X           | X       | X                | X     | X     |       |       |         |
| BSA                                                                     | X (SOC)     | (SOC)   | (SOC)            | (SOC) | (SOC) | (SOC) | (SOC) | X (SOC) |
| X                                                                       | X           | X       | X                | X     | X     |       |       |         |
| Performance status                                                      | X (SOC)     | (SOC)   | (SOC)            | (SOC) | (SOC) | (SOC) | (SOC) | X (SOC) |
| Adverse event  evaluation                                               | X           | X       | X                | X     | X     | X     | X     |         |
| Study Assessments Troponin I                                            | X           | X       | X                | X     | X     |       |       |         |  
49
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14.0 references

1.U.S. Cancer Statistics Working Group. *United States Cancer Statistics: 1999–2009* Incidence and Mortality Web-based Report. Atlanta (GA): Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2013. Available at: http://www.cdc.gov/uscs. 2. Gianni L et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375(9712):377-84. 3. Schneeweiss, A et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-84. 4. Gianni, L et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. The Lancet Oncol. 2012; 13 (1): 25 - 32. 5. Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, 2012. 6. McArthur, H et al. Neoadjuvant trial design: time for a brave new world? Nature Reviews. 2010; 7: 359-360. 7.Rastogi, P et al. Preoperative Chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27, J Clin Oncol. 2008; 26:778-785.  
8. van der Hage, J et al.Preoperative Chemotherapy for Women With Operable Breast Cancer, Cochrane Database of Systematic Reviews. 2007, 2, Art. No: CD005002. 9. Bear et al. Sequential Preoperative or Postoperative Docetaxel Added to Preoperative Doxorubicin Plus Cyclophosphamide for Operable Breast Cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006; 24(13): 2019-2027. 10. Guidance for Industry Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval. U.S. Department of Health and Human Services.Food and Drug Administration. Center for Drug Evaluation and Research (CDER). May 2012.  
11. Dawood S. et al. Prognosis of Women With Metastatic Breast Cancer by *HER2* Status and Trastuzumab Treatment: An Institutional-Based Review.. J Clin Oncol. 2010; 28 (1) 92-98. 12.von Minkwitz, G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol.2012; 30: 1796- 1804. 13. Untch M. et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol. 2010;28(12):2024-2031. 14. Robidoux et al. Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: NSABP protocol B-41. J Clin Oncol. 2012; suppl; abstr LBA506. 15. Swain et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. The Lancet Oncology.2013; 14 (6): 461 - 471. 16. Geyer H et al. Assessment of myocardial mechanics using speckle tracking echocardiography: fundamentals and clinical applications. J Am Soc Echocardiogr.2010; 23(4):351-369. 17.Sengupta PP, Narula J. Reclassifying heart failure. Heart Fail Clin. 2008;4(3):37982. 18. Sawaya H et al. Assessment of Echocardiography and Biomarkers for the Extended Prediction of Cardiotoxicity in Patients Treated with Anthracyclines, Taxanes, and Trastuzumab. Circ Cardiovasc Imaging. 2012; 5: 596-603.  
19. Sawaya et al. Early detection and prediction of cardiotoxicity in chemotherapytreated patients. Am J Cardiol. 201;107(9):1375-1380.  
20. Negishi K et al. Independent and Incremental Value of Deformation Indices for Prediction of Trastuzumab-Induced Cardiotoxicity.J Am Soc Echocardiogr. 2013; 3: S0894-7317. 21. Morris et al. Troponin I and C-Reactive Protein Are Commonly Detected in Patients with Breast Cancer Treated with Dose-Dense Chemotherapy Incorporating Trastuzumab and Lapatinib. Clin Cancer Res. 2011; 17 (10): 3490-3499. 22. NCCN Guidelines 23. http://www.asco.org/advocacy/fda-approves-pertuzumab-neoadjuvant-breastcancer 24. Slamon et al, Adjuvant Trastuzumab in HER2-Positive Breast Cancer (BCIRG 006). N Engl J Med 2011; 365:1273-1283. 25. Citron ML et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003; 21(8):1431-1439. 26. Capelan et al. Pertuzumab: new hope for patients with HER2-positive breast cancer. Annals of Oncology. 2012; 0: 1–10.  
27. Rexer et al. Direct inhibition of PI3K in combination with dual HER2 inhibitors is required for optimal antitumor activity in HER2+ breast cancer cells Breast Cancer Research.2014; 16 (1):1-14.  
28. Carracedo et al. The PTEN–PI3K pathway: of feedbacks and cross-talks.  
Oncogene. 2008; 27: 5527–5541 29.Yamaguchi et al. Signaling cross-talk in the resistance to HER family receptor targeted therapy. Oncogene. 2014; 33: 1073–1081. 30. Cardinale D, Sandri MT, Martinoni A et al. Myocardial injury revealed by plasma troponin I in breast cancer treated with high-dose chemotherapy. Ann Oncol 2002; 13: 710–715. 31. Cardinale D et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high dose chemotherapy. Circulation. 2004; 109:27492754. 32. Tan-Chiu E. et al. Assessment of Cardiac Dysfunction in a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel, With or Without Trastuzumab As Adjuvant Therapy in Node-Positive, Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer: NSABP B-31. J Clin Oncol. 2005; 23 (31) 7811-7819. 33. Mackey JR et al. Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian Trastuzumab Working Group. Curr Oncol. 2008; 15(1): 24–35.  
  
If 3 or fewer patients have a pCR, then that arm will be terminated and no further patients will be entered on that treatment arm. If 4 or more patients obtain a pCR, 20 additional patients (total of 37 patients) will be randomized to that treatment arm.
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appendix b notification to cardiology

Please note: this patient is on a study as above. Please calculate patient's Ejection Fraction (EF) as well as longitudinal strain and document it here and in the report. Patient Name:
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patient mrn local protocol id#

(*A Phase II Randomized Trial Evaluating Neoadjuvant Dose-Dense* Doxorubicin/Cyclophosphamide followed by Paclitaxel/Trastuzumab/Pertuzumab Compared with Docetaxel/Carboplatin/Trastuzumab/Pertuzumab For Early Her2Neu Positive Breast Cancer)
Documentation: : (or attach report)Patient's EF:
Patient's calculated longitudinal strain:
*please return completed form to Dr. Aarti Bhardwaj MD via email with subject "protocol EF and longitudinal strain"
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appendix c blood serum troponin

o Samples should be obtained at protocol specified time points 1 using supplies available onsite, specifically a green top tube.  
o The minimum amount of sample required is 0.15cc of blood.  
o All specimens should be sent to the institution's central lab immediately for processing as per their standard of practice.
1. Troponin I serum measurements will be performed at screening for baseline, right before chemotherapy is administered (time "0"), 24 hrs after start of chemotherapy, within 1 month of time
"0" and within 3 months of time "0" for duration of both regimens until surgery. Most of these scheduled troponin measurements will be done within 24 hours of chemotherapy administration See Study calendar.
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local protocol id#

(*A Phase II Randomized Trial Evaluating Neoadjuvant Dose-Dense* Doxorubicin/Cyclophosphamide followed by Paclitaxel/Trastuzumab/Pertuzumab Compared with Docetaxel/Carboplatin/Trastuzumab/Pertuzumab For Early Her2Neu Positive Breast Cancer) Documentation: 1.Please circle one Total pCR or Residual disease Appendix E. Serious Adverse Event Reporting Form SERIOUS ADVERSE EVENT REPORTING FORM  
| 1 - Trial Information  SPONSOR  OVERALL PRINICPAL INVESTIGATOR  LOCAL PRINCIPAL INVESTIGATOR  IRB NUMBER STUDY TITLE 2 - About the event  Are you reporting a UP? (Unanticipated Problem)   | Yes                  | No           |              |        |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|--------------|--------------|--------|
| 3 - SAE report type  Report type                                                                                                                                                            | Initial notification | Follow up    |              |        |
| 4 - About the time of the event Date Investigator informed                                                                                                                                  | Date of report       |              |              |        |
| Date of Onset                                                                                                                                                                               | Date Resolved        |              |              |        |
| 5 - Participant information  SUBJECT ID NUMBER                                                                                                                                              | Age                  | Gender       | Male         | Female |
| 6 - Description of Event                                                                                                                                                                    | Seriousness          | Causality    | Expectedness |        |
| Death                                                                                                                                                                                       | Not related          | Expected     |              |        |
| Life threatening                                                                                                                                                                            | Unlikely             | Not expected |              |        |
| Hospitalization or prolongation of hospital stay                                                                                                                                            | Possibly             |              |              |        |
| Persistent or significant disability or incapacity                                                                                                                                          | Probably             |              |              |        |  
| Congenital abnormality or birth defect                | Definitely   |
|-------------------------------------------------------|--------------|
| Otherwise considered serious                          |              |
| Brief description of event  [] Check if Cardiac Event |              |  
Diagnosis  
| Outcome Fatal                                                                                                           | On-going   | Recovered with sequelae   | Recovered   |
|-------------------------------------------------------------------------------------------------------------------------|------------|---------------------------|-------------|
| If recovered (or recovered with sequelae) selected, enter date of recovery If fatal enter date of death Cause of death: |            |                           |             |  
| Information about the CHEMOTHERAPY/ STUDY DRUG Drug (please specify action taken next to the agent) Legend is in the last column         | Dose       | Route   | Start date   | Stop date   | Action Taken 1- Dose stopped 2- Dose reduced 3- Dose unchanged 4- Dose increased   |                                                                                         |
|------------------------------------------------------------------------------------------------------------------------------------------|------------|---------|--------------|-------------|------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|
| Relevant Concomitant Medication Drug (please specify action taken)                                                                       | Indication | Dose    | Route        | Start date  | Stop date                                                                          | Action Taken 1- Dose stopped 2- Dose reduced 3- Dose unchanged 4- Dose increased 5- N/A |
| Other clinical information, including relevant tests (laboratory, CT, ECG etc.) **Please include relevant redacted source documentation. |            |         |              |             |                                                                                    |                                                                                         |  
7 - Medication details 60 61