Specific potential safety issues for this trial are outlined below. 3.4.1 Cardiac Dysfunction CONFIDENTIAL Page 18 of 102 Protocol: HERCEPTIN® + E75/GM-CSF Version 3.1 ML25749 05 March 2017 Signs and symptoms of cardiac dysfunction were observed in a number of women who received Herceptin alone or in combination with chemotherapy, most often anthracycline-based treatment. Cardiac dysfunction was observed most frequently among patients who received Herceptin plus AC chemotherapy (28%), compared with those who received AC alone (7%), Herceptin plus paclitaxel (11%), paclitaxel alone (1%), or Herceptin alone (7%). Severe disability or fatal outcome due to cardiac dysfunction was observed in ~1% of all patients. The nature of the observed cardiac dysfunction was similar to the syndrome of anthracycline-induced cardiomyopathy. The signs and symptoms of cardiac dysfunction usually responded to treatment. Complete and partial responses were observed among patients with cardiac dysfunction. The risk appears to be independent of tumor response to therapy. Analysis of the clinical database for predictors of cardiac dysfunction revealed only advanced age and exposure to an anthracycline as possible risk factors. In the clinical trials, most patients with cardiac dysfunction responded to appropriate medical therapy, often including discontinuation of Herceptin. In many cases, patients were able to resume treatment with Herceptin. In a subsequent study using weekly paclitaxel and Herceptin as first-line treatment for metastatic breast cancer, the observed incidence of serious cardiac dysfunction was 3% (n=95) (Seidmen et al. 2001). Since the occurrence of cardiac dysfunction in the Herceptin plus chemotherapy trial was an unexpected observation, no information is available regarding the most appropriate method for monitoring cardiac function in patients receiving Herceptin. Significant advances in the understanding and treatment of CHF have been made in the past several years, with many of the new drugs demonstrating the ability to normalize cardiac function. Patients who develop symptoms of CHF while on Herceptin should be treated according to the HFSA guidelines (Appendix D). 3.4.2 Management of Cardiac Safety 3.4.2.1 Adjuvant Breast Cancer Protocols All patients must have a cardiac assessment at baseline (MUGA preferred, ECHO allowed, consistency required), and on a regular schedule throughout the course of the study. Investigators are strongly urged to schedule cardiac assessment studies at the same radiology facility where the patient’s baseline assessment was done whenever possible. Cardiac assessment studies are required at protocol-specified time points and after any patient has any of the following: discontinuation of protocol therapy, CHF, breast cancer recurrence, or a second primary cancer. Post-surgical radiation therapy may be required in patients at risk for recurrence. Whenever possible, irradiation to the internal mammary nodes should be avoided because of the concern for possible additional cardiotoxicity from the combination of Herceptin and radiation therapy. Efforts should be taken to ensure that the volume of the heart irradiated is minimal. Investigators are encouraged to discuss cardiac toxicity concerns with their radiation oncologists to ensure careful planning of the ports of left-sided lesions. CONFIDENTIAL Page 19 of 102 Protocol: HERCEPTIN® + E75/GM-CSF Version 3.1 ML25749 05 March 2017 Cardiac Safety Criteria for initiation of Herceptin Asymptomatic Patients If a patient does not have significant symptoms related to left ventricular (LV) dysfunction, administration of Herceptin will depend on the absolute change in LVEF between baseline and follow-up assessments. Herceptin should be initiated in an asymptomatic patient if: a) The LVEF increased or stayed the same b) The LVEF decreased by ≤15 percentage points but is still at or above the lower limit of normal for the radiology facility Herceptin is PROHIBITED in an asymptomatic patient if: a) The LVEF decreased ≤15 percentage points and is below the limit of normal for the radiology facility b) The LVEF decreased by 16 percentage points or more (regardless of lower limits of normal for the radiology facility) Symptomatic Patients If a patient has significant symptoms related to LV dysfunction, cardiac ischemia, or arrhythmia, initiation of Herceptin is prohibited. Management of Symptomatic Cardiac Changes.