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5.2.2.3 management of infections

From a historical perspective, everolimus has been in clinical development since 1996 initially in solid organ transplantation as a medication to prevent rejection. It has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis and viral infections including reactivation of hepatitis B virus, have been described in patients taking everolimus. Some of these infections have been severe (e.g. leading to respiratory or hepatic failure) and occasionally have had a fatal outcome. In the phase III study of everolimus in patients with advanced pancreatic neuroendocrine tumors, infectious complications of any grade were seen in 23% (predominantly in the upper respiratory tract; grade 3 or 4, 2%) in the investigational arm vs. 6%
(grade 3 or 4, <1%) in the placebo arm116. On the other hand though, no infectious adverse events were reported in the clinical study that compared letrozole +/- everolimus in the neoadjuvant setting4.  
57 Physicians and patients should be aware of the increased risk of infection with everolimus. Preexisting infections should be appropriately treated prior to starting the investigational therapy. While  
  
taking everolimus, the patient and the investigator should be vigilant for symptoms and signs of infection. If a diagnosis of infection is made, appropriate treatment should be instituted promptly and, if the infection is severe enough, interruption or discontinuation of everolimus should be considered. If a diagnosis of invasive systemic fungal infection is made, everolimus will be discontinued; the patient will be taken off study and treated with appropriate antifungal therapy. Cases of pneumocystis jirovecii pneumonia (PJP), some with a fatal outcome, have been reported in patients who received everolimus. PJP may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis for PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.
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5.2.2.4 management of skin toxicity

For patients with grade 1 toxicity, no specific supportive care is usually needed or indicated. Rash must be reported as an AE. Patients with grade 2 or higher toxicity may be treated with the following suggested supportive measures at the discretion of the investigator: oral minocycline, topical tetracycline, topical clindamycin, topical silver sulfadiazine, diphenhydramine, oral prednisolone (short course), topical corticosteroids, or pimecrolimus.
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5.2.2.5 management of hypersensitivity reactions

Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus.
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5.2.2.6 angioedema with concomitant use

Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment).
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5.2.2.7 renal failure events

Cases of renal failure (including acute renal failure), some with fatal outcome, occurred in patients treated with everolimus. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function. Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients taking everolimus. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of everolimus therapy and periodically thereafter.
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5.2.2.8 management of diarrhea

Appearance of grade 1-2 diarrhea attributed to study drug toxicity may be treated with supportive care such as loperamide, initiated at the earliest onset (for example 4 mg orally followed by 2 mg orally every 2 hours until resolution of diarrhea).  
5.2.2.9 **Cytochrome P450 and P-glycoprotein inhibitors/inducers/substrates**
Co-administration with strong inhibitors of CYP3A4 or P-gp should be avoided; and may cause increased everolimus concentrations. For a current table of Substrates, Inhibitors and Inducers please access the following website: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractions Labeling/ucm093664.htm. Everolimus is metabolized by CYP3A4 in the liver and to some extent in the intestinal wall. Therefore, the following are recommended:
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir)
or P-glycoprotein (P-gp) inhibitor should be avoided.  
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or P-gp inhibitors should be used with caution. If a patient requires co-administration of moderate CYP3A4 inhibitors or P-gp inhibitors, reduce the dose of everolimus by approximately 50%. Additional dose reductions to every other day may be required to manage toxicities. If the inhibitor is discontinued, the Everolimus dose should be returned to the dose used prior to initiation of the moderate CYP3A4/P-gp inhibitor after a washout period of 2 to 3 days.  
Grapefruit, Seville oranges, and star fruit affect P450 and P-gp activity. Concomitant use should be avoided.  
If patients require co-administration of a strong CYP3A4 inducer, consider doubling the daily dose of Afinitor (based on pharmacokinetic data), using increments of 5 mg or less. This dose of Afinitor is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued, consider a washout period of at least 3 to 5 days (reasonable time for significant enzyme de-induction), before the Afinitor dose is returned to the dose used prior to initiation of the strong CYP3A4 inducer.  
This dose adjustment of Everolimus is intended to achieve similar AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the Everolimus dose should be returned to the dose used prior to initiation of the strong CYP3A4/P-gp inducer.  
Please refer to **Table 5-11** listing relevant inducers and inhibitors of CYP3A and **Table 5-12** for a list of relevant substrates, inducers, and inhibitors of P-gp.
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everolimus and drugs influencing cyp3a4

Everolimus is a substrate of CYP3A4, and a substrate and moderate inhibitor of the multidrug efflux pump, P-gp (P-gp, MDR1, and ABCB1). Therefore, extent of absorption and subsequent elimination of systemically absorbed everolimus may be influenced by products that are substrates, inhibitors, or inducers of CYP3A4 and/or P-gp. Concurrent treatment with strong CYP3A4-inhibitors should be avoided. Refer to **Table 5-8** in section 6 for a comprehensive list of inducers and inhibitors of CYP3A4 and **Table 5-9** for a list of relevant substrates, inducers and inhibitors of P-gp. Inhibitors of P-gp may decrease the efflux of everolimus from brain or tumor and therefore increase everolimus concentrations in these tissues. In vitro studies showed that everolimus is a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing the concentrations of products eliminated by these enzymes. Thus, caution should be exercised when co-administering everolimus with CYP3A4 and CYP2D6 substrates with a narrow therapeutic index. Clinical studies have been conducted in healthy subjects to assess pharmacokinetic drug interactions between everolimus and potential CYP3A modifiers (ketoconazole, verapamil, erythromycin, rifampin, midazolam, and HMGCoA reductase inhibitors (statins).  
Table 5-11: Clinically relevant drug interactions: inducers, and inhibitors of isoenzyme CYP3A
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inducers

Strong inducers: avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. John's Wort (hypericum perforatum)
Moderate inducers: bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir,
[talviraline], thioridazine, tipranavir Weak inducers: amprenavir, aprepitant, armodafinil (R-modafinil), bexarotene, clobazam, danshen, dexamethasone, Echinacea, garlic (allium sativum), gingko (ginkgo biloba), glycyrrhizin, methylprednisolone, nevirapine, oxcarbazepine, pioglitazone, prednisone, [pleconaril], primidone, raltegravir, rufinamide, sorafenib, telaprevir, terbinafine, topiramate, [troglitazone] , vinblastine Inhibitors Strong inhibitors: boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole117, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, troleandamycin, voriconazole Moderate inhibitors: Amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, cyclosporine, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, grapefruit juice (citrus parasidi fruit juice), imatinib, schisandra sphenanthera, tofisopam, verapamil Table 5-12: Clinically relevant drug interactions: substrates, inducers,  
  
inhibitors of P-gp **and P-gp/CYP3A dual inhibitors**
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rifampin st john's wort p-gp

amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar, erythromycin, felodipine, fexofenadine, fluvoxamine, ginkgo (ginkgo biloba), indinavir, itraconazole, lopinavir, mibefradil, milk thistle (silybum marianum), nelfinavir, nifedipine, nitrendipine, paroxetine, quercetin, quinidine, ranolazine, rifampin, ritonavir, saquinavir, Schisandra chinensis, St John's Wort (hypericum perforatum), talinolol, Telaprevir, telmisartan, ticagrelor, tipranavir, tolvaptan, valspodar, verapamil Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 2, 2011,29-Oct2012 which summarizes DDI data from three sources including the FDA's "Guidance for Industry, Drug Interaction Studies", the University of Washington's Drug Interaction Database, and Indiana University School of Medicine's Drug Interaction Table.
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5.2.2.10 vaccinations

Immunosuppressants may affect the response to vaccination and vaccination during treatment with Everolimus may therefore be less effective. The use of live vaccines should be avoided during treatment with Everolimus. For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations prior to the start of therapy according to local treatment guidelines. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
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5.2.3 trc105

Description of the drug. TRC105 is a chimeric anti-CD105 IgG1 antibody consisting of human Cκ and Cγ1 constant regions with murine Vκ and VH regions. TRC105 is composed of two light chains of 213 amino acids and two heavy chains of 448 amino acids and has an approximate molecular weight of 148 kDa. Manufacturing. A high producing CHO cell line using media that is free of animal derived components has been developed for production of TRC105. The TRC105 currently in use in all clinical studies is CHO-produced. The manufacturing process uses conventional purification and filtration steps and concludes with the formulation of TRC105 in 20 mM L-Histidine/L-Histidine Monohydrochloride, 240 mM Trehalose, 0.01% Polysorbate 20 Formulation (25 mg TRC105/mL)85.  
Pharmacokinetic properties. In the phase 1 first-in-human dose escalation study of TRC105, the medication was detectable at all dose levels immediately after intravenous infusion35. In patients enrolled at doses below 0.3 mg/kg every 2 weeks, circulating TRC105 was detectable but not measurable above the lower limit of quantitation of the assay (78 ng/mL). On an every 2-week 61  
schedule, TRC105 was measurable above the target concentration that saturates CD105 receptors (200 ng/mL) for a duration of 4 hours at a TRC105 dose of 0.3 mg/kg, for 24 hours at 1 mg/kg, 120 hours at 3 mg/kg, and 188 hours at 10 mg/kg (Fig. 1). The observed terminal T½ was considerably prolonged following a single dose of 15 mg/kg compared with 3 and 10 mg/kg. Serum concentrations expected to saturate CD105 binding sites (≥200 ng/mL) were achieved continuously at 15 mg/kg dosed every 2 weeks and 10 mg/kg dosed weekly. At doses above 1 mg/kg, AUC increased supraproportionally with dose, whereas the Cmax seemed to be dose proportional35. TRC105 clearance was consistent with target mediated disposition, and decreased clearance at higher doses was related to target saturation85.  
Immunogenicity.. Neither Human anti-murine antibody (HAMA) nor Human anti-chimeric antibody (HACA) were detected in patients treated with CHO-produced TRC105 which was administered at the 0.3, 1, 3, 10 and 15 mg/kg dose levels35,85 and will be used in the proposed study. Pharmacodynamic properties. Please refer to the investigational brochure85 for nonclinical pharmacodynamics studies with TRC105. The dose for TRC105 is 15 (cohorts 1 and 2) or 10 (cohort -1) mg/kg IV every two weeks and it will be continued until 4 **weeks prior to surgery**. Adverse events. The most common adverse events associated with TRC105 are infusion reactions that are successfully mitigated with premedications and prolongation of the infusion time, hemorrhages (mostly grade 1 and 2), headaches, and hypoproliferative anemia35. See section 8.3 for additional information regarding TRC105 adverse events.
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5.2.3.1 management of infusion reactions

Infusion reactions have been observed following TRC105 administration, usually with the initial dose (including a grade 4 vasovagal reaction that resolved without sequelae), and were commonly associated with one or more of the following signs or symptoms: hypertension, hypotension, dyspnea, bronchospasm, chills/rigors, chills, sweats, fever, nausea, tachycardia, bradycardia, EKG changes, flushing, urticaria, pruritus, and headache, generally of grade 1 and 2 severity. Hypersensitivity reactions with infusions are a potential risk for sensitized patients, and TRC105 should be used with caution in patients with known hypersensitivity to any component of the drug product. Host antiTRC105 antibodies to the murine or human portions of CHO-produced TRC105 are rare. In general, the risk of immunogenicity to therapeutic chimeric antibodies is small (<10%). The presence of HAMA of HACA neither correlated nor predicted the development of infusion reactions.  
By extending the duration of the initial infusion from one to four hours and adding a glucocorticoidbased premedication regimen prior to each dose, the frequency and severity of infusion reactions were reduced. At dose levels where continuous TRC105 serum levels were achieved, with subsequent infusions dexamethasone was safely discontinued and the infusion duration reduced to one hour. **Table 5-10** provides guidelines for the definition and management of infusion related reactions.  
To mitigate or avoid infusion reactions associated with TRC105, the following actions will be undertaken: a. The first dose of TRC105 will be split in two separate infusions to be infused over 4 hours each on days 1 (3 mg/kg) and 4 (12 mg/kg or 7 mg/kg if dose de-escalation occurs). If well tolerated, all subsequent infusions will be administered as a whole (i.e., 15 mg/kg or 10 mg/kg if dose deescalation occurs) in their scheduled times and infusion time will gradually be reduced to 2 hours and then to a minimum of 90 minutes.  
b. The following TRC105 premedications should be administered 2 hours to 30 minutes prior to the start of each infusion:
1. Acetaminophen 650 mg p.o. x 1 2. Methylprednisolone 100 mg i.v.. In the absence of any infusion reaction with the prior dose, methylprednisolone may be discontinued beginning with cycle 3. In addition, methylprednisolone will be given in the case of a delay of ≥ 18 days between any two doses or if the patient develops an infusion reaction during the immediate prior infusion.  
3. Famotidine 20 mg i.v. or p.o. (or similar H2 blocker) x 1. Famotidine (or similar H2 blocker) may be discontinued starting with Cycle 2 in the absence of infusion reactions with the prior dose.  
4. Cetirizine 10 mg i.v. or p.o. x 1 (or similar oral or intravenous antihistamine). Cetirizine
(or similar oral or intravenous antihistimine) may be discontinued starting with Cycle 2 in the absence of infusion reactions with the prior dose.  
c. During the first (day 1 and 4) infusion, vital signs should be checked every 30 minutes and methylprednisolone 100 mg IV should be readily available for infusion.  
| Grade                                                                                      | Signs or                                                                                                                   | Recommended Action                                                                                                                                      | Dose Adjustment or                                                                                                |
|--------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|
| Symptoms                                                                                   | Modification                                                                                                               |                                                                                                                                                         |                                                                                                                   |
| Grade 1 Mild transient  reaction                                                           | Mild increase in  heart rate but <100  bpm Mild increase in  respiratory rate but  <25 breaths per  minute                 | Interruption not  indicated Intervention not  indicated                                                                                                 | None                                                                                                              |
| Grade 2 Infusion interruption  indicated but  responds promptly to  symptomatic  treatment | Increase in heart  rate but<120 bpm Increase in  respiratory rate but  <30 breaths per  minute Skin rash or mild  pruritus | Withhold infusion until  resolution of symptoms  but no less than 30  minutes.  Administer  methylprednisolone 100  mg IV ±  diphenhydramine 50 mg  IV. | None  Premedications as per  cycle 1. Do not shorten  subsequent infusions  until no infusion  reactions are seen |  
|                                                                                                                                                    | UAB 1514 / Version 7-25-19                                                                                                                                                                                                                            |                                                                                                                                                           |
|----------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|
| Resume infusion once  symptoms resolve                                                                                                             |                                                                                                                                                                                                                                                       |                                                                                                                                                           |
| Grade 3 Prolonged recurrence  of symptoms  following initial  improvement;  hospitalization  indicated                                             | None  Escalate  premedications to  dexamethasone 8 mg  PO BID in the day  before and day of  chemotherapy. Do not shorten  subsequent infusions  until no infusion  reactions are seen. If the reaction recurs  the patient will be taken  off study. |                                                                                                                                                           |
| Grade 4 Life-threatening  consequences                                                                                                             | Increase in heart  rate >120 bpm,  palpitations and  sense of  "impending  doom" Diffuse skin rash and pruritus Tachypnea >30  breaths per minute  and mild wheezing                                                                                  | Interrupt infusion and do  not resume.  Administer  methylprednisolone 250  mg IV and  diphenhydramine 50 mg  IV.  Admit to the hospital for  observation |
| Palpitations,  tachycardia,  dyspnea with  stridor or  wheezing, sense of  "impending  doom", chest pain,  diffuse rash with  wheals and  pruritus | Interrupt infusion and  admit to the MICU Administer  methylprednisolone 250  mg IV and  diphenhydramine 50 mg  IV. Administer pressors  as indicated.                                                                                                | Do not rechallenge with  TRC105. The patient  will be taken off study.                                                                                    |
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5.2.3.2 management of hemorrhages

Grade 3 or 4 hemorrhage with TRC105 is rare. In the phase I study, one patient developed doselimiting toxicity of grade 4 hemorrhage presenting as melena from a gastric ulcer within 5 days of the initial TRC105 infusion at 0.1 mg/kg35. TRC105 was withheld, the patient was transfused 2 units of packed red blood cells and the bleeding resolved with nonsurgical management by the time of upper endoscopy. Patients with bleeding gastrointestinal ulcers or other sources of bleeding will be excluded from the study unless there is documentation of healing. Subsequent bleeding associated with TRC105 has been limited to low grades including superficial gingival bleeding, epistaxis, and intermittent post-coital vaginal bleeding in a patient with uterine cancer recurrent at the vaginal cuff. Gingival bleeding and epistaxis are related to the development of mucocutaneous telangiectasia and represent on-target effects of TRC105 therapy. Patients with epistaxis may benefit from saline nasal gel. All patients treated with TRC105 should be monitored for signs of hemorrhage and the risks and benefits of drug treatment reevaluated in any patient with hemorrhage.  
Cerebrovascular hemorrhage (grade 3) resulting in hemiparesis occurred in one patient with hepatocellular cancer who was thrombocytopenic (platelet count of 60,000/uL) in a study of TRC105 with sorafenib. Patients in TRC105 protocols are required to have platelet counts of 100,000/µL.  
Accrual will be halted as a result of any grade ≥3 hemorrhage, cerebrovascular and vasovagal adverse events; FDA will be contacted to discuss further accrual or potential need for protocol amendment.
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5.2.3.3 management of anemia

Hypoproliferative anemia was the dose-limiting toxicity in the phase I study35 and may be related to the action of TRC105 on proerythroblasts, the only cells in the bone marrow known to express high levels of CD105. When hemoglobin drops in a patient on the study, it is important to investigate for any ongoing blood loss. A reticulocyte count should be obtained to document the hypoproliferative nature of the anemia associated with TRC105. Anemia should be managed with standard supportive measures including transfusions of packed red blood cells if deemed necessary. If grade 3 or higher treatment related anemia develops, the dose of TRC105 should be reduced from 15 mg/kg to 10 mg/kg or held if the assigned dose is 10 mg/kg until resolution of the anemia.
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5.2.3.4 management of headache

Headaches (grade 1 to 3) have been observed following TRC105 treatment, generally within hours following completion of the initial infusion. Headaches are throbbing in nature, have not been associated with radiographic abnormalities, and have responded to treatment with non-steroidal antiinflammatory agents (including ketorolac) and to triptans. Extending the infusion to 4 hours or interrupting the infusion may also by tried to mitigate the headaches Nasal congestion and periorbital edema have been observed with TRC105. The edema has been transient in nature and treated with corticosteroids. Antihistamines are useful for nasal congestion.
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5.2.4 goserelin

Description of the drug: Goserelin (Zoladex®) is a synthetic decapeptide analog of endogenous gonadotropin-releasing hormone. GnRH regulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis and secretion by the anterior pituitary gland, which in turn stimulates the production of estrogens by the ovary. In response to GnRH, FSH and LH synthesis initially increases, causing a transient increase in circulating levels of sex hormones. These hormones are however, regulated by feedback loops, so further hormone release is suppressed. Chronic administration of goserelin leads to sustained suppression of pituitary gonadotropins FSH and LH as the pituitary gland down-regulates and desensitizes GnRH receptors.  
Pharmacodynamic properties: Within 3 weeks following initial administration of goserelin, serum estradiol is suppressed to levels similar to those observed in postmenopausal women. However, after suppression was attained, isolated elevations of estradiol were seen in up to 10% of the patients enrolled in clinical trials. Serum LH and FSH are suppressed to follicular phase levels within four weeks after initial administration of drug and are usually maintained at that range with continued use of goserelin. In 5% or less of women treated with goserelin, FSH and LH levels may not be suppressed to follicular phase levels on day 28 post treatment with a single 3.6 mg depot injection. Pharmacokinetic properties: Goserelin in its depot formulation is released slowly initially for the first 8  
days, and then there is more rapid and continuous release for the remainder of the 28-day dosing period. Despite the change in the releasing rate of goserelin, administration of goserelin every 28 days resulted in testosterone levels that were suppressed to and maintained in the range normally seen in surgically castrated men. When goserelin 3.6 mg depot was used for treating male and female patients with normal renal and hepatic function, there was no significant evidence of drug accumulation. However, in clinical trials the minimum serum levels of a few patients were increased. These levels can be attributed to interpatient variation. The apparent volumes of distribution determined after subcutaneous administration of 250 μg aqueous solution of goserelin was 20.3 liters for females. The plasma protein binding of goserelin obtained from one sample is 27.3%.  
Metabolism of goserelin, by hydrolysis of the C-terminal amino acids, is the major clearance mechanism. All metabolites found in humans have also been found in toxicology species. Clearance of goserelin following subcutaneous administration of the solution formulation of goserelin is very rapid and occurs via a combination of hepatic metabolism and urinary excretion. More than 90% of a subcutaneous radiolabeled solution formulation dose of goserelin is excreted in urine. Approximately 20% of the dose in urine is accounted for by unchanged goserelin. (AstraZeneca, Package Insert). Goserelin is generally safe to administer with other medications. Goserelin should be administered subcutaneously every 28 days into the anterior abdominal wall below the navel line using an aseptic technique under the supervision of a physician.
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5.2.5 concomitant medications

The reason(s) for treatment dosage, and dates of treatment should be recorded in the source documents. Concomitant medications should be reported to the investigator and will be recorded as instructed in the study specific case report forms. Patients who experience TRC105-related temperature elevations or other infusion-related symptoms may be treated symptomatically with acetaminophen, dyphenhydramine, meperidine, or other medications as clinically indicated, including < 48 hours of treatment with corticosteroids. Patients should receive full supportive care, including transfusions, antibiotics, anti-emetics, etc. when appropriate. Pre-trial supportive care will continue. The following therapies are excluded during active protocol therapy: radiotherapy, hormonal therapy different from the agent prescribed in the protocol, cytotoxic chemotherapy, herbal medicines and cancer immunotherapy or other biologic agents. If the patient is on low dose aspirin at baseline he/she may continue it if medically indicated. If the patient is on NSAIDs on study should also receive peptic ulcer disease (PUD) prophylaxis with an H2 or proton pump blocker. Packed red blood cell, colony stimulating factors, and platelet transfusions should be administered as clinically indicated.
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5.3 dose modifications and delays

Dose modifications and delays are allowed. Determinations to reduce the dose, withhold, or delay the administration of a drug rely on the treating physician. The choice of the drug(s) (letrozole and/or everolimus and/or TRC105, or all three components) that need(s) to be withheld or dose reduced (everolimus or TRC105; delays but no dose reductions are allowed for letrozole) relies on the treating  
physician and should be based on the nature of the observed adverse events. The justification for dose modifications and delays should be clearly documented. The maximum duration that a patient is allowed to withhold up to all three medications of the regimen is 7 days. Treatment can be resumed after 7 days at a lower dose level as outlined below for each individual component of the regimen. If treatment cannot be resumed within 7 days, the patient will be taken off study.
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5.3.1 dose modifications and delays

Modifications. The dose of letrozole will not be modified (increased or decreased) in this protocol. Also letrozole cannot be substituted for another hormonal agent (e.g. anastrozole). Delays. The maximum duration that a patient is allowed to withhold letrozole due to adverse events is 7 days. If a patient cannot resume letrozole after 7 days or it is deemed necessary to withhold the medication again, the patient will be taken off study.
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5.3.2 dose modifications and delays

Modifications. The dose for everolimus is 5 or 10 mg PO daily. In patients receiving 10 mg PO daily, dose reduction to 5 mg PO daily is allowed for adverse events or intolerance at the discretion of the treating physician. The reason for dose reduction must be clearly documented. Dose reductions at levels below 5 mg PO daily are allowed to 2.5 mg PO. No further reductions are allowed. Dose adjustments should be made if a patient's hepatic (Child-Pugh) status changes during treatment.  
Mild hepatic impairment (Child-Pugh A) - if the assigned dose was 5 or 10 mg PO daily, the recommended dose is 2.5 and 7.5 mg PO daily, respectively.  
Moderate hepatic impairment (Child-Pugh B) - if the assigned dose was 10 mg PO daily, the recommended dose is 5 mg daily. If the assigned dose was 5 mg PO daily, withhold everolimus until resolution of hepatic impairment and resume at 5 mg PO daily.  
Severe hepatic impairment (Child-Pugh C) - not recommended. If the desired benefit outweighs the risk, a dose of 2.5 mg daily must not be exceeded.
Delays. The maximum duration that a patient is allowed to withhold everolimus due to adverse events is 7 days. If a patient cannot resume everolimus after 7 days or it is deemed necessary to withhold the medication again, the patient will be taken off study.  
5.3.3 **Dose modifications and delays with TRC105**
Modifications. The dose for TRC105 is 10 or 15 mg/kg IV every two weeks and it will be continued until 4 weeks prior to surgery. Dose reductions to 10 mg/kg due to adverse events are allowed and the justification(s) should be documented. Dose reductions below 10 mg/kg are not allowed and if deemed necessary, the patient will be taken off study. Delays. All infusions of TRC105 should be administered within 3 days of the protocol-specified schedule. The maximum duration that a patient is allowed to withhold TRC105 due to adverse events is 14 days. If TRC105 is delayed > 3 days the first dose of TRC105 following the break needs to be split into two doses; 3 mg/kg should be given on the first day and the remainder of the dose (i.e., 12 mg/kg, or 7 mg/kg in the case of a dose de-escalation) will be given 3 days later and the  
methylprednisolone dose should be reinstituted. If a patient cannot resume TRC105 after 14 days or it is deemed necessary to withhold the medication again, the patient will be taken off study. Resumption at 10 mg/kg if the subject was receiving 15 mg/kg are allowed with the reinstitution of full premedication, as specified in Section 5.2.3.1.
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5.3.4 dose modifications and delays

Modifications. No dose modifications are allowed with goserelin Delays: delays up to 3 days are allowed to accommodate for scheduling issues, inclement weather, or other extraneous circumstances.
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5.4 study procedures 5.4.1 screening

Informed consent will be obtained before study-specific screening evaluations are performed. Screening evaluations must be performed within 4 weeks prior to day 0. Results of tests or examinations done as standard of care prior to obtaining informed consent and within 56 days prior to day 0 may be used rather than repeating tests. The following evaluations and procedures will be performed during the screening phase: - Signed informed consent. - Clinical evaluations: medical history, demographics, weight and height, complete physical examination, vital signs and performance status.  
- Determination of the surgical procedure to be performed at the time of diagnosis without the neoadjuvant treatment by the surgical oncologist in the multidisciplinary team. Determinations include unresectable (for locally advanced disease that cannot be adequately resected unless tumor shrinkage is achieved), mastectomy, and lumpectomy.  
- Laboratory assessment: UA, CBC with differential and platelet count, serum chemistries
(glucose, BUN, creatinine, total protein, albumin, bilirubin, calcium, alkaline phosphatase, AST, and ALT), serum electrolytes (Na, K, Cl), ferritin, and a lipid panel (cholesterol, triglycerides, HDL, and LDL) in a fasting state (at least 8 hours).  
- Determination of menopausal status: FSH, LH, and estradiol levels. - Pregnancy test in women with childbearing potential. - Research biopsy (core needle biopsy of the tumor) (required). - Sentinel lymph node biopsy if required. - Estrogen and Progesterone receptor status.  
 - Her-2-neu by immunohistochemistry and or FISH (Negative: IHC 0, 1 or 2+ or non-amplified by FISH).  
- Tumor assessments: Mammogram and breast ultrasound are required. PET/CT scan or CT scan of chest, abdomen, pelvis, with bone scan will be obtained. If the scan shows disease outside the breast and/or the axilla, the patient will not be enrolled in the trial.  
- 12-lead EKG. Evaluation of the ejection fraction with an echocardiogram or MUGA, if clinically indicated.  
- Concomitant medication assessment. - Patients who have satisfied basic eligibility criteria will be assigned with a study patient number and the patient can proceed to be consented.  
- Hepatitis B and C panels (see 5.2.2.3, table 5-2 and table 5-4 for Hepatitis B and C interpretation).
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5.4.1.1 screening for hepatitis b

Prior to initiation of Everolimus, the following three categories of patients should be tested for hepatitis B viral load and serologic markers, that is, HBV-DNA, HBsAg, HBs Ab, and HBc Ab:
All patients who currently live in (or have lived in) Asia, Africa, Central and South America, Eastern Europe, Spain, Portugal and Greece.  
[http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-totravel/hepatitis-b.htm]
Patients with any of the following risk factors:
known or suspected past hepatitis B infection, blood transfusion(s) prior to 1990, current or prior IV drug users, current or prior dialysis, household contact with hepatitis B infected patient(s),
current or prior high-risk sexual activity, body piercing or tattoos, mother known to have hepatitis B
history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper quadrant pain Additional patients at the discretion of the investigator.  
The management guidelines, in 5.2.2.3, are provided according to the results of the baseline assessment of viral load and serological markers for hepatitis B.
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5.4.1.2 screening for hepatitis c

Patients with any of the following risk factors for hepatitis C should be tested using quantitative RNA-PCR:
known or suspected past hepatitis C infection (including patients with past interferon 'curative' treatment),
blood transfusions prior to 1990, current or prior IV drug users, current or prior dialysis, household contact of hepatitis C infected patient(s),
current or prior high-risk sexual activity, body piercing or tattoos At the discretion of the investigator, additional patients may also be tested for hepatitis C. The management guidelines, in 5.2.2.3, are provided according to the results of the baseline assessment of hepatitis C viral load.
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5.4.1.3 pregnancy and assessments of

There are no adequate data from the use of everolimus and TRC105 in pregnant women. The safety of women of childbearing capacity cannot be implied for the existing data with TRC105. Studies with everolimus in animals have shown reproductive toxicity effects including embryo-toxicity and feto-toxicity. The potential risk for humans is unknown. Everolimus should not be given to pregnant women unless the potential benefit outweighs the potential risk to the fetus. If a pregnancy occurs while on study treatment, the newborn will be followed for at least 12 months. It is not known whether everolimus is excreted in breast milk. However, in animal studies everolimus and/or its metabolites readily passed into the milk of lactating rats. Women taking everolimus should therefore not breast-feed.
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women of childbearing potential

Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and for 8 weeks after stopping treatment. Highly effective contraception is defined as either:
Total abstinence: When this is in line with the preferred and usual lifestyle of the subject.  
[Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]
Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment  
Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). [For female subjects on the study, the vasectomised male partner should be the sole partner for that subject].  
Use of a combination of any two of the following (a+b or a+c or b+c):
a. Use of oral, injected, implanted or other hormonal methods of contraception b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository In case of use of oral contraception, women should have been stable on the oral agent before taking study treatment.
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male contraception

Sexually active males must use a condom during intercourse while taking the drug and for 8 weeks after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Female partners of male patients must also be advised to use one of the following contraception methods: Use of (1) oral, injected, implanted or other hormonal methods of contraception, or (2) intrauterine device (IUD) or intrauterine system (IUS), or (3) prior male/female sterilization.
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fertility

The potential for everolimus and TRC105 to cause infertility in male and female patients is unknown. However, menstrual irregularities, secondary amenorrhea and associated luteinizing hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed with everolimus. Based on non-clinical findings, male and female fertility may be compromised by treatment with everolimus and TRC105.
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5.4.2 treatment phase

The following evaluations and procedures will be performed during the **treatment phase**: (All assessments should be performed within 5 working days of the protocol-specified date). - Physical examination, vital signs, weight, and performance status on weeks 4, 8, 12, 16, 20 and 24.  
- Laboratory assessments: CBC with differential and platelet count, serum chemistries (glucose, BUN, creatinine, total protein, albumin, bilirubin, calcium, alkaline phosphatase, AST, and ALT), and serum electrolytes (Na, K, Cl) on week 1 and at the beginning of each cycle until week 24.  
- Lipid panel (cholesterol, triglycerides, HDL, and LDL) in a fasting state (at least 8 hours) should be obtained at least on cycle 2 and, if elevated, repeated on each cycle until recovery to baseline value or grade 1 (see 5.2.2.2 for management of hyperlipidemia and hyperglycemia).  
Serum estradiol levels on weeks 4, 12, and 20 in women receiving goserelin. - Hepatitis panel as clinically indicated. - Research biopsy (core needle biopsy of the tumor) at week 4 (required). - Tumor assessments: Ultrasound of the breast will be obtained on week 4, 8, 12, 16, 20 and 24.  
Mammogram will be obtained on week 24. Additional PET scans or CT of the chest, abdomen, and pelvis, or bone scans are not required during treatment phase except as clinically indicated
(see section **7.2 Measurement of Effect**). MRI breast will be obtained at baseline, week 12 and 24.  
- Evaluation of the ejection fraction with an echocardiogram/MUGA only as clinically indicated. - Surgical evaluation at the end of neoadjuvant therapy. There must be at least 4 weeks between the last dose of everolimus and TRC105 **and surgery**. Patients will continue letrozole until the day before surgery.  
- Concomitant medication assessment. - Assessment of adverse events.
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5.4.3 safety follow-up phase

Patients will complete participation in the protocol at the time of surgery and will not be followed unless the patient requires follow up of adverse events. The following evaluations and procedures will be performed at **early termination.** Every effort should be undertaken for the following procedures to be completed within 10 days. - Clinical evaluations: Weight, physical examination (complete), vital signs and performance status. There must be a complete and clear documentation of objective response or disease progression using the RECIST criteria. Reason(s) for discontinuation must be documented.  
- Laboratory assessment: UA, CBC with differential and platelet count, serum chemistries
(glucose, BUN, creatinine, total protein, albumin, bilirubin, calcium, alkaline phosphatase, AST, and ALT), serum electrolytes (Na, K, Cl), and lipid panel (cholesterol, triglycerides, HDL, and LDL) in a fasting state (at least 8 hours).  
- Tumor assessments: Mammogram, breast ultrasound, and breast MRI. Spiral CT scans of chest, abdomen, and pelvis, bone scan, and any other procedure are not required per protocol but will be obtained if clinically indicated.  
- Concomitant medication assessment. - Assessment of adverse events. If the patient has an ongoing toxicity, the patient should be followed until resolution or stabilization. Serious and non-serious adverse events occurring  
within 30 days of day 0 of the last treatment should be reported on the appropriate adverse event CRF.
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5.5 study termination

The principal investigator retains the right to terminate study participation in consultation with the other investigators in the study. The principal investigator will notify the institutional review board and FDA in writing of the early termination or completion of the study and keep a copy of the notification in the regulatory file. Circumstances that may raise consideration for early termination include but are not limited to: inordinate toxicity of the proposed combination that is not amenable to protocol amendment, and slow accrual (rate of accrual of less than 1 patient in 6 months).
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5.6 subject discontinuation

Patients may withdraw from this study at any time. Any patient who withdraws will be encouraged to return to the study center for the post-dose evaluations. The termination visit consists of all evaluations scheduled for the termination visit. The primary reason(s) for discontinuation must be recorded on the appropriate CRF page. The PI may discontinue a patient from treatment. Reasons may include, but are not limited to, the following: progressive disease, failure to obtain postmenopausal status (defined as serum estradiol levels any time during treatment in the premenopausal range) clinically significant deterioration, noncompliance, persistent grade 3 or 4 adverse event or any significant adverse event that compromises the patient's ability to participate in the study, requirement of a significant surgical procedure or radiation therapy during the treatment period of the study, investigator's determination that it is not in the patient's best interest to continue participation, anemia greater than grade 4, persistent grade 3 mucositis despite maximal supportive care, development of brain metastases, pregnancy. Patients who have an ongoing grade 4 or serious adverse event at the time of discontinuation from study treatment will continue to be followed at least weekly for 4 weeks and at least monthly thereafter at the discretion of the investigator until resolution of the event or until the event is considered irreversible.
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6. study drug preparation and

| Drug                                                                                                   | Formulation                       | Dose and Route    | Frequency   |
|--------------------------------------------------------------------------------------------------------|-----------------------------------|-------------------|-------------|
| Letrozole                                                                                              | Tablet for oral use               | 2.5 mg PO         | Daily       |
| Everolimus                                                                                             | Tablet for oral use               | 5 or 10 mg PO     | Daily       |
| TRC105                                                                                                 | Solution for intravenous infusion | 10 or 15 mg/kg IV | q 2 weeks*  |
| Goserelin**                                                                                            | Depot for subcutaneous injection  | 3.6 mg            | q 4 weeks   |
| subcutaneously                                                                                         |                                   |                   |             |
| * The first infusion of TRC105 will be split in 2 separate infusions to be administered on cycle 1 day |                                   |                   |             |
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6.1 dosing regimen and schedule

Table 6-1: **Dosing regimen and schedule**
* The first infusion of TRC105 will be split in 2 separate infusions to be administered on cycle 1 day 1 (3 mg/kg) and cycle 1 day 4 (12 or 7 mg/kg). ** when applicable
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6.1.2 trc105 preparation

TRC105 will be prepared in the pharmacy and diluted into normal saline using appropriate aseptic technique. TRC105 will be administered using an in-line 0.2 micron filter. No incompatibilities between TRC105 and polyvinyl chloride or polyolefin bags have been observed. Multiple vials will be required for a single dose. The following formulae should be used to calculate the volume of TRC105 to be added to normal saline:
Patient weight (kg) × dose level (mg/kg) divided by TRC105 concentration (mg/mL) =
volume of TRC105 (mL) to be administered.  
The volume of TRC105 that is to be administered can be rounded up or down to the nearest 1.0 mL; in the case of an increment of 0.5 mL the volume should be rounded up. The maximum weight that should be used for dose calculation in this study is 85 kg (note: there is not a weight restriction for enrollment purposes). If the patient's weight changes by > 10% during the study, the dose of TRC105 will be recalculated. At that time a new baseline weight will be established such that subsequent weight changes by >10% from the new baseline weight would require further recalculation of the TRC105 dose. The calculated volume of TRC105 will be diluted with normal saline. Appropriate judgment should be exercised in withdrawing an adequate amount of saline necessary to permit injection of the appropriate volume of antibody into a normal saline bag in accordance with the dose needed. The final TRC105 concentration must be between 0.3 mg/mL and 10 mg/mL. The prepared TRC105 must be gently inverted several times in order to ensure a homogeneous solution. The diluted infusion solution of TRC105 should be used within 8 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2°C to 8°C (36º to 46ºF). The expiration time should be labeled on the bag. If the diluted infusion solution of TRC105 cannot be infused within 8 hours of preparation (i.e.: the prepared infusion is at room temperature for more than 8 hours), a second bag will be prepared that contains the balance of the planned dose that was not already delivered. The prepared solution should not be frozen. 6.1.3 TRC105 Administration  
Patients should be encouraged to drink abundant fluid (e.g. two eight ounce glasses of water or juice) prior to the first treatment. Intravenous hydration prior to and during therapy is left to the discretion of the Investigator, but should be considered if the patient is thought to be volume depleted. The following TRC105 premedications should be administered 2 hours to 30 minutes prior to the start of each infusion:
Acetaminophen 650 mg p.o. x 1  
Methylprednisolone 100 mg i.v. In the absence of any infusion reaction with the prior dose, methylprednisolone may be discontinued beginning with **cycle 3.** In addition, methylprednisolone will be given in the case of a delay of ≥ 18 days between any two doses or if the patient develops an infusion reaction during the immediate prior infusion.  
Famotidine 20 mg i.v. or p.o. (or similar H2 blocker) x 1. Famotidine (or similar H2 blocker) may be discontinued starting with Cycle 2 in the absence of infusion reactions with the prior dose.  
Cetirizine 10 mg i.v. or p.o. x 1 (or similar oral or intravenous antihistamine).  
Cetirizine (or similar oral or intravenous antihistimine) may be discontinued starting with Cycle 2 in the absence of infusion reactions with the prior dose.
TRC105 will be administered intravenously utilizing an infusion pump. TRC105 has been demonstrated to be compatible with polyethylene lined, non-DEHP infusion sets and polyvinyl chloride, non-DEHP infusion sets. TRC105 is required to be administered with a 0.2 micron downstream filter. The attachment of the infusion pump administration set to the i.v. bag and transport of the TRC105 study drug to the patient will be performed as per standard study site procedures. Following the appropriate premedication regimen, the patient will receive TRC105 on day 1 and day 15 of every cycle. The first TRC105 dose will be split with 3 mg/kg administered on cycle 1 day 1 and infused over 4 hours (+/- 15 minutes) and 12 mg/kg (or 7 mg/kg if dose is de-escalated) administered on cycle 1 day 4 and infused over 2 hours (+/- 15 minutes), and then the full dose of 15 mg/kg (or 10 mg/kg if dose is de-escalated) given on cycle 1 day 15 and every 2 weeks thereafter and will be administered over a minimum of 90 minutes. The patient must complete at least one 4 hour infusion (+/- 15 minutes) without the development of any infusion reactions, in order to reduce the subsequent TRC105 infusion to 2 hours (+/- 15 minutes) and complete a 2 hour infusion (+/- 15 minutes) without the development of any infusion reactions in order to reduce subsequent TRC105 infusions to a **minimum of 90 minutes**. If the patient develops infusion reactions of any kind they should be managed appropriately (see Section 5.3.2.1) and the patient is not permitted to reduce the duration of the next planned infusion. The rate of TRC105 infusion must not exceed 25 mg/min. When the i.v. bag containing TRC105 is empty, flush the i.v. line with a 20 mL normal saline. The dose level, time of transfer to i.v. bag, and the infusion start and stop times must be recorded in the source documents.  
If the patient misses a TRC105 dose (i.e., ≥ 18 days between doses), the full premedication (including methylprednisolone) should be reinstituted as per the initial infusion and TRC105 dose should be administered over two days as was done for the initial dose.
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6.2 drug formulations

All dosages prescribed and dispensed to the patient and all dose changes during the study must be recorded. Medication labels will comply with US legal requirements and be printed in English. They will supply no information about the patient.
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6.2.1 letrozole formulation

Commercially available tablets of letrozole will be used in the study. Complete guidelines for the management and administration of letrozole can be found in the package insert (http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020726s027lbl.pdf). Letrozole will not be provided from the study
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6.2.2 everolimus formulation

Everolimus is formulated as tablets for oral administration of 2.5mg, 5mg, and 10mg strength. Tablets are blister-packed under aluminum foil, which should be opened only at the time of administration as drug is both hygroscopic and light-sensitive. Everolimus should be administered orally once daily at the same time every day, either consistently with or consistently without food. Refer to label for expiration date and storage conditions. The extent of absorption of everolimus through topical exposure is not known. Therefore, caregivers are advised to avoid contact with suspensions of everolimus Tablets. Hands should be washed thoroughly before and after preparation of either suspension. The blisters for everolimus tablets should be opened only at the time of administration as the formulation is both hygroscopic and lightsensitive. Storage conditions for everolimus are described on the medication label
(http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022334s021s023s024,203985s002s004 s005lbl.pdf). The study drugs should be stored in a secure, locked area while under the responsibility of the principal investigator. Receipt and dispensing of study drug must be recorded by an authorized person at the investigator's site. The tablets should be swallowed whole with a glass of water and should not be chewed or crushed. For patients unable to swallow tablets, the tablet(s) should be dispersed completely in a glass of water (containing approximately 30 mL) by gently stirring until the tablet(s) is fully disintegrated (approximately 7 minutes), immediately prior to drinking. The glass should be rinsed with the same volume of water and the rinse completely swallowed to ensure the entire dose is administered. If vomiting occurs, no attempt should be made to replace the vomited dose. Patients should be instructed that if they miss a dose on one day, they must not take any extra dose the next day, but instead to immediately contact the study center as soon as possible to ask for advice. Everolimus will be provided from the study.
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6.2.3 trc105 formulation

| labeled with the following: TRC105 NSC# 754227 100 mg per vial (25 mg/mL, 4 mL per vial) Store refrigerated at 2-8˚C.  For Intravenous Use Only. Single-use vial. Lot: XXXXXXX Mfg Date: XX/XX/XXXX Caution: New Drug Limited by  Federal (or United States) law to investigational  use. TRACON Pharmaceuticals Inc., San Diego, CA  92122 USA   | TRC105 NSC# 754227 400 mg per vial (25 mg/mL, 16 mL per vial) Store refrigerated at 2-8˚C.  For Intravenous Use Only. Single-use vial. Lot: XXXXXXX Mfg Date: XX/XX/XXXX Caution: New Drug Limited by  Federal (or United States) law to investigational  use. TRACON Pharmaceuticals Inc., San Diego, CA  92122 US   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
TRC105 will be provided by TRACON Pharmaceuticals, Inc.
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6.2.4 goserelin formulation

Goserelin is supplied as a sterile, biodegradable product containing goserelin acetate equivalent to 3.6 mg of goserelin. Goserelin is designed for subcutaneous injection with continuous release over a 28-day period. Goserelin acetate is dispersed in a matrix of D,L-lactic and glycolic acids copolymer (13.3-14.3 mg/dose) containing less than 2.5% acetic acid and up to 12% goserelin-related substances and presented as a sterile, white to cream colored 1-mm diameter cylinder, preloaded in a special single use syringe with a 16-gauge x 36 +/- 0.5 mm siliconized needle with protective needle sleeve
(SafeSystem™ Syringe) in a sealed, light and moisture proof, aluminum foil laminate pouch containing a desiccant capsule. Studies of the D,L-lactic and glycolic acids copolymer have indicated that it is completely biodegradable and has no demonstrable antigenic potential (AstraZeneca, Package Insert).
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6.3 study drug storage and

Study treatments must be received by designated personnel at the study site, handled and stored safely and properly, and kept in a secured location to which only the investigator and designated site personnel have access. Upon receipt, the study treatment should be stored according to the instructions outlined in section 6.2.
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6.4 study drug compliance

The investigator should promote compliance by instructing the patient to take the study drug exactly as prescribed and by stating that compliance is necessary for the patient's safety and the validity of  
the study. The patient should be instructed to contact the investigator if he/she is unable for any reason to take the study drug as prescribed. Compliance will be assessed by the investigator and/or study personnel at each patient visit and information provided by the patient and/or caregiver. Records of study medication used, dosages administered, and intervals between visits and the completion of the study will be captured in the Drug Accountability Form. This information must be captured in the source document at each patient visit. On PK sampling days, compliance will be assured by administration of the study treatment under the supervision of investigator or his/her designee, and will be verified by determination of letrozole, everolimus, and TRC105 in serum.
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6.5 study drug accountability

The investigator or designee must maintain an accurate record of the shipment and dispensing of study treatment in a drug accountability log. Patients will be asked to return all unused study treatment and packaging at the end of the study or at the time of study treatment discontinuation. At study termination, and, as appropriate during the course of the study, the investigator will return all used and unused study treatment, packaging, drug labels, and a copy of the completed drug accountability log to the Novartis and TRACON monitor or to the Novartis and TRACON address provided in the investigator folder at each site.
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7. visit schedule and assessments

Figure F and **table 7-1** (following page) list all the assessments and indicate with an "x" the times they need to be performed. Baseline evaluations are to be conducted within 1week prior to start of protocol therapy. Imaging studies must be done within 4 weeks prior to the start of therapy. In the event that the patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. For all visits except day 1, there is a temporal window of ±3 days to account for holidays, inclement weather or other extraneous circumstances. The temporal window does not apply for PK sampling, which needs to be undertaken at the specified time frames. Every effort must be undertaken to follow this schedule. In patients who discontinue their treatment early, all procedures outlined in 5.4.3 (5.4.3 **Safety** Follow-up Phase) must occur within 10 days. Patients who complete the protocol treatment and proceed to surgery as planned do not need to have an end of treatment visit.  
  
Premenopausal women at the time of study enrollment will receive goserelin 3.6 mg subcutaneously q 4 weeks to achieve ovarian suppression.
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7.2 measurement of effect

Although response is not the primary endpoint of this trial, patients with measurable disease will be  
  
assessed by standard criteria. **Patients must have disease that can be measured and followed by**
mammogram and/or breast ultrasound. Dedicated breast MRI evaluation will be done baseline, week 12 and 24. For the purposes of this study, patients should be re-evaluated every 4 weeks.
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7.2.1 antitumor effect

Response and progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST)118 Committee
(http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf)
118. Changes in only the largest diameter (one-dimensional measurement) of the tumor lesions are used in the RECIST criteria.  
Table 7-1: Study Calendar (see **5.4 Study Procedures**)  
  
| SC                             | Treatment Phase11, 13   | End of                                                                                                                                                                                                             |      |       |      |       |      |       |      |       |      |       |           |
|--------------------------------|-------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------|-------|------|-------|------|-------|------|-------|------|-------|-----------|
| treatment7                     |                         |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| C1D1                           | C1D4                    | C1D15                                                                                                                                                                                                              | C2D1 | C2D15 | C3D1 | C3D15 | C4D1 | C4D15 | C5D1 | C5D15 | C6D1 | C6D15 | Follow up |
| Informed consent               | X                       |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| Demographics                   | X                       |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| Inclusion/Exclusion            | X                       |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| Past Medical History           | X                       |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| History Present Illness        | X                       |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| Concurrent Medications         |                         | X----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X             |      |       |      |       |      |       |      |       |      |       |           |
| Prior therapy                  | X                       |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| Physician Visits               | X                       | X                                                                                                                                                                                                                  | X    | X     | X    | X     | X    | X     | X    |       |      |       |           |
| Physical Examination           | X                       | X                                                                                                                                                                                                                  | X    | X     | X    | X     | X    | X     | X    |       |      |       |           |
| Performance status             | X                       | X                                                                                                                                                                                                                  | X    | X     | X    | X     | X    | X     | X    |       |      |       |           |
| Vital Signs                    | X                       | X                                                                                                                                                                                                                  | X    | X     | X    | X     | X    | X     | X    |       |      |       |           |
| Height/Weight                  | X                       | X                                                                                                                                                                                                                  | X    | X     | X    | X     | X    | X     | X    |       |      |       |           |
| CBC and differential           | X                       | X                                                                                                                                                                                                                  | X    | X     | X    | X     | X    | X     | X    |       |      |       |           |
| Chemistries/Electrolytes       | X                       | X                                                                                                                                                                                                                  | X    | X     | X    | X     | X    | X     | X    |       |      |       |           |
| FSH, LH,estradiol levels       | X                       |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| Estradiol levels15             | X                       | X                                                                                                                                                                                                                  | X    |       |      |       |      |       |      |       |      |       |           |
| Pregnancy test14               | X                       |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| Lipid panel1                   | X                       | X                                                                                                                                                                                                                  |      |       |      |       |      |       |      |       |      |       |           |
| Hepatitis panel2               | X                       |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| Urinalysis3                    | X                       |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| 12-lead EKG                    | X                       |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| Serum ferritin level           | X                       |                                                                                                                                                                                                                    |      |       |      |       |      |       |      |       |      |       |           |
| Everolimus serum level         | X 10                    | X 10                                                                                                                                                                                                               |      |       |      |       |      |       |      |       |      |       |           |
| TRC105 serum level             | X 10                    | X 10                                                                                                                                                                                                               |      |       |      |       |      |       |      |       |      |       |           |
| Anti-TRC105 antibodies (APA)11 | X                       | X                                                                                                                                                                                                                  | X    | X     | X    | X     | X 11 |       |      |       |      |       |           |
| VEGF-A serum12                 | X                       | X                                                                                                                                                                                                                  | X    | X     |      |       |      |       |      |       |      |       |           |
| sEng / TGf-β serum12           | X                       | X                                                                                                                                                                                                                  | X    | X     |      |       |      |       |      |       |      |       |           |
| Angiopoietin-1/2 serum12       | X                       | X                                                                                                                                                                                                                  | X    | X     |      |       |      |       |      |       |      |       |           |
| Research Biopsy4               | X                       | X                                                                                                                                                                                                                  | X    |       |      |       |      |       |      |       |      |       |           |
| Adverse Events                 |                         | X----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X81 | P a g e |      |       |      |       |      |       |      |       |      |       |           |  
| Mammography       | X   | X                                                                                                                                                                                       |    |    |    |    |    |    |    |    |    |    |    |
|-------------------|-----|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|----|----|----|----|----|----|----|----|----|----|
| Breast ultrasound | X   | X                                                                                                                                                                                       | X  | X  | X  | X  | X  |    |    |    |    |    |    |
| Breast MRI5       | X   | X                                                                                                                                                                                       | X  |    |    |    |    |    |    |    |    |    |    |
| Body CT/MRI/PET6  | (X) |                                                                                                                                                                                         |    |    |    |    |    |    |    |    |    |    |    |
| Letrozole8        |     | X- -------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------------X |    |    |    |    |    |    |    |    |    |    |    |
| Everolimus9       |     | X-------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------X |    |    |    |    |    |    |    |    |    |    |    |
| TRC1059           | X   | X                                                                                                                                                                                       | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  | X  |
| Goserelin13       | X   | X                                                                                                                                                                                       | X  | X  | X  | X  |    |    |    |    |    |    |    |
| Surgery           | X   |                                                                                                                                                                                         |    |    |    |    |    |    |    |    |    |    |    |  
Notes:  
  
  
1. Cholesterol, triglycerides, HDL, and LDL in a fasting state (8 hours) should be obtained at least on cycle 2 and, if elevated, repeat on each cycle until recovery to baseline value or grade 1.  
2. Hepatitis panel should be obtained on screening and repeated as clinically indicated (HBV-DNA, HBsAg, HBs Ab, and HBc Ab, and RNAPCR).  
3. Urinalysis should be obtained on screening and repeated as clinically indicated. 4. Research biopsy (core needle biopsy of the tumor). 5. Breast MRI is required by the protocol. 6. As clinically indicated after baseline diagnosis. 7. Within a week of surgery. 8. Continuation until the day prior to surgery. 9. Continuation no later than 4 weeks prior to surgery. 10. Samples will be collected and concentrations of the agents measured on cycles 1 and 2 at the following time points: pre-dose, 1, 2, 4, 6, and 24, hours, and cycle 1 day 4 pre-dose.  
11. TRC105 anti-product antibodies (APA) will be collected before dosing on cycle 1 day 1, every 4 weeks thereafter, 4 and 12 weeks following the last dose of TRC105.  
12. Markers of angiogenesis (VEGF-A, soluble VEGFR2, activin A and activin B, angiopoietin-1 and -2, TGF-β, soluble endoglin) will be measured on samples collected pre-dose, cycle 1 day 15, cycle 2 day 1, and prior to surgery.  
13. Administered only if FSH, LH, and estradiol NOT within postmenopausal range at the time of enrollment. 14. In women with childbearing potential 15. Only in women receiving goserelin
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7.2.2 definitions

Evaluable for toxicity. All patients who receive at least one dose of any or all of the drugs of the investigational regimen will be evaluable for toxicity from the time of their first treatment until discontinuation or completion of the investigational therapy. Evaluable for objective response. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below.
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7.2.3 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 with conventional techniques (mammogram, breast ultrasound, exceptionally MRI). All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Note: Tumor lesions that are situated in a previously irradiated area should not be considered measurable. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with conventional techniques), are considered non-measurable disease. For this protocol it will be satellite lesions in the affected breast. Target lesions (not applicable for this trial). All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of breast(s) involved, 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) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor response. Non-target lesions (not applicable for this trial. All other lesions including any measurable lesions over and above the 10 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 or absence of each should be noted throughout follow-up.
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7.2.4 evaluation of response reporting

Studies in the neoadjuvant setting in breast cancer have used various endpoints in the assessment of response including rates of pCR12,59,60,119, radiographic response1, and clinical response4,14,17.  
Although these endpoints may have their limitations, the rates of pCR is the outcome measure least subject to serious errors of measurement and interpretation. All three outcome measures will the recorded and reported. The following definitions will be used:  
a. Clinical response: the target lesion will be clinically assessed and measured using calipers on each visit. At least 2 dimensions will be measured and recorded. The maximum reduction in the maximum dimension of the tumor from baseline will be recorded as the best clinical response.  
b. Radiographic response: the target lesion(s) will be measured and recorded at least in 2 dimensions on mammograms, breast ultrasound, and MRI. RECIST will be used to assess the best radiographic response (see below 7.2.5 **Methods for Evaluation of Measurable Disease**).  
c. Pathologic response: the 2-dimensional size of the surgically excised residual tumor will be measured and compared to the radiographic size of the tumor at baseline. The maximum dimension will be used for comparison.  
Definition of pathologic complete remission (pCR): the definition adopted by the Center for Drug Evaluation and Research of the FDA104 will be used to define and report pCRs. According to the Center for Drug Evaluation and Research of the FDA, a pCR is defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0 ypN0 in the current AJCC staging system)104. For this protocol, near pCR will be considered if the breast residual disease is less or equal to 0.5 cm.
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7.2.5 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. Evaluation by clinical examination will always be complemented by imaging evaluation. See **Appendix C** for guidelines issued by the American College of Radiology for imaging studies of the breast. In cases of discrepancy between clinical and radiographic evaluation by >1 cm, a complementary imaging technique (breast ultrasound when the mammograms are inconclusive and breast MRI when both mammograms and breast ultrasound are inconclusive) will be used for the initial and subsequent assessments of the target lesion(s).
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7.2.5.1 clinical assessments

Target lesion(s) in the breast or target ipsilateral lymph nodes will be measured using calipers and the size in two dimensions will be recorded on each clinical visit.
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7.2.5.2 mammography

Standard diagnostic mammograms will be used to identify and follow the target lesion(s) during the course of the protocol treatment. All mammograms will be obtained at the Kirklin Clinic which meets the requirements set forth by the Mammography Quality Standards Act (MQSA) final rule published by the Federal Drug Administration (FDA). Technical considerations of diagnostic mammography (The American College of Radiology Practice Guideline for the Performance of Screening and Diagnostic Mammography, http://www.acr.org/~/media/3484ca30845348359bad4684779d492d.pdf): 1. A diagnostic mammogram will include mediolateral oblique (MLO), craniocaudal (CC), and/or supplemental views to evaluate an area of clinical or radiographic concern. 2. Supplemental mammographic views might include spot compression, spot compression with magnification, tangential views, or other special views.  
3. When selecting a view, the proximity of the area of concern to the image receptor should be considered. 4. Diagnostic mammography should be performed under the immediate supervision of the interpreting physician.
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7.2.5.3 breast ultrasound

Breast ultrasound (US) is particularly helpful in further delineating findings on mammography. All breast ultrasounds will be obtained at the Kirklin Clinic to complement diagnostic mammograms. Technical considerations of Breast Ultrasonography (The American College of Radiology Practice Guideline for the Performance of a Breast Ultrasound Examination, http://www.acr.org/~/media/52D58307E93E45898B09D4C4D407DD76.pdf) 1. The breast sonogram should be correlated with clinical signs and/or symptoms and with mammographic and other appropriate breast imaging studies. If sonography has been performed previously, the current examination should be compared with prior sonograms. A lesion or any area of the breast being studied should be viewed in 2 perpendicular projections, and real-time scanning by the interpreter is encouraged.  
2. The size of a lesion should be determined by recording its maximal dimensions in at least 2 planes; orthogonal planes are recommended. At least 1 set of images of a lesion should be obtained without calipers. 3. The images should be labeled as to right or left breast, location of lesions, and the orientation of the transducer with respect to the breast (e.g., transverse or longitudinal, radial or antiradial). The location of the lesion should be recorded using clock face notation and distance from the nipple, and/or shown on a diagram of the breast. The length of the transducer face (footprint), usually between 3.5 cm and 5 cm, can be used to estimate the distance from the nipple. Measurements should not be made from the edge of the areola, as areolar width is widely variable. 4. Sonographic features are helpful in characterizing breast masses. These feature categories and their descriptors are listed and exemplified in the ACR Breast Imaging Reporting and Data System® (BIRADS®). The BI-RADS sonographic categories include size, shape, orientation, margin, 86  
echogenicity, lesion boundary, attenuation (e.g., shadowing or enhancement), special cases, vascularity, and surrounding tissue120.  
5. Elastography, or tissue stiffness assessment, is among the new feature categories applicable to sonographic analysis of masses, to be included in the Associated Findings section in BI-RADS Ultrasound, edition 2. To minimize errors in communication or interpretation, if elastography is performed, the color scales should be annotated to denote hardness or softness. 6. Mass characterization with ultrasonography is highly dependent on technical factors. Breast ultrasound should be performed with a high-resolution scanner. Gain settings, focal zone selections, and fields of view should be optimized to obtain high-quality images. The patient should be positioned to minimize the thickness of the portion of the breast being evaluated. For evaluation of lesions in, on, or just beneath the skin, a stand-off device or thick layer of gel may be helpful
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7.2.5.4 breast magnetic resonance imaging

Breast Magnetic Resonance Imaging (MRI) is required by the protocol. Technical considerations of Breast MRI (The American College of Radiology Practice Guideline for the Performance of Contrast-Enhanced Magnetic Resonance Imaging [MRI] of the Breast, http://www.acr.org/~/media/2A0EB28EB59041E2825179AFB72EF624.pdf) 1. Resolution, contrast, and field strength: Although a 1.5T magnet has traditionally been considered a minimum technical requirement because of the relationship between field strength and resolution, improvements in other components of the scanning process have resulted in improved scan quality at lower field strengths. High spatial and temporal resolutions are needed to detect and characterize small abnormalities on MRI. The slice thickness should be 3 mm or less, and in-plane pixel resolution should be 1 mm or less to minimize the problem of volume averaging effects. Optimized contrast between tumor and surrounding tissue is important. When high-resolution images are being obtained, chemical fat suppression is helpful as a method to reduce fat signal while preserving the signal-tonoise ratio. Sole reliance on subtraction imaging for assessment of enhancement may result in misregistration due to patient motion; use of fat suppression is recommended on sequences used to assess contrast enhancement. Protocols may incorporate both fatsuppression and subtraction. Motion correction may be helpful in reducing artifacts encountered with image subtraction. 2. Contrast: Gadolinium contrast enhancement is generally needed in the evaluation of breast cancer. Gadolinium contrast should be administered as a bolus with a standard dose of 0.1 mmol/kg followed by a saline flush of at least 10 ml. 3. Scan time: A pre-contrast scan should be obtained. Scan time in relation to contrast injection is extremely important for lesion characterization. Kinetic information should be reported, based on enhancement data determined at specified intervals separated by 4 minutes or less. Imaging sites should have adequately short temporal resolution for accurate capture of lesion kinetics. 4. Examinations should be performed with a dedicated bilateral breast MRI coil.  
Tumor markers. Tumor markers alone cannot be used to assess response and will not be routinely obtained in the course of the study. Patients with stage III breast cancer will undergo imaging studies including imaging studies dedicated to identify skeletal metastases (bone scan and/or bone surveys) to confirm absence of metastatic disease.
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7.2.6 response criteria 7.2.6.1 evaluation

Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
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7.2.6.2 evaluation of non-target lesions

Complete Response (CR): Disappearance of all non-target lesions. Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s). Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions 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).
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7.2.6.3 evaluation of best overall

The best overall response is the best response recorded from the start of the treatment until completion of protocol treatment, early termination, or 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.  
| Target Lesions   | Non-Target Lesions   | New                     | Overall   | Best Response for this        |
|------------------|----------------------|-------------------------|-----------|-------------------------------|
| Lesions          | Response             | Category Also Requires: |           |                               |
| CR               | CR                   | No                      | CR*       | NA for this trial88 | P a g e |  
|     | UAB 1514 / Version 7-25-19                                                                                                                                                           |           |      |                                               |
|-----|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------|------|-----------------------------------------------|
| CR  | Non-CR/Non-PD                                                                                                                                                                        | No        | PR** | NA for this trial                             |
| PR  | Non-PD                                                                                                                                                                               | No        | PR   |                                               |
| SD  | Non-PD                                                                                                                                                                               | No        | SD   | Documented at least once > 4 wk from baseline |
| PD  | Any                                                                                                                                                                                  | Yes or No | PD   |                                               |
| Any | PD***                                                                                                                                                                                | Yes or No | PD   | No prior SD, PR or CR                         |
| Any | Any                                                                                                                                                                                  | Yes       | PD   |                                               |
| *   | For the definition of a pCR please refer to section 7.3.1.3. Definition of pathologic complete  remission (pCR). No subsequent confirmation is required for pCR. ** Residual disease |           |      |                                               |  
***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.
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7.2.7 duration of response

Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for clinical CR or PR (whichever is first recorded) until completion of protocol treatment or early termination or 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 clinical CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until completion of protocol treatment or early termination or the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.
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7.3 pharmacokinetic and pharmacodynamic studies

Figure G provides an outline of the planned pharmacokinetic and pharmacodynamics studies and the time or research biopsy.  
Figure G
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7.3.1 pharmacokinetic (pk) and anti-product

To investigate the pharmacokinetic interaction between TRC105 and everolimus, samples will be collected and concentrations of the agents measured on cycle 1 day 1 and cycle 2 day 1 at the following time points: predose, 1, 2, 4, 6, 24 hours, and cycle 1 day 4 pre-dose. Pharmacokinetic parameters to be estimated include maximum serum concentration (Cmax), time of maximum serum concentration (Tmax), area under the serum concentration versus time curve (AUC), terminal half-life (T½), and clearance. Serum for assessment of TRC105 anti-product antibody (APA) formation will be collected before dosing on cycle 1 day 1, every 4 weeks thereafter, 4 and 12 weeks following the last dose of TRC105 and concentrations will be determined by a validated ELISA53.
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7.3.2 pharmacodynamic (pd) studies

Markers of angiogenesis (VEGF-A, soluble VEGFR2, activin A and activin B, angiopoietin-1 and -
2, TGF-β, soluble endoglin) will be measured on serum samples collected predose, cycle 1 day 15, cycle 2 day 1, and prior to surgery.
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7.3.3 research biopsies

Formalin-fixed paraffin embedded tissue blocks from the patient's primary tumor collected for diagnostic purposes will be requested for all patients enrolled in the study at the time of registration. In addition, a research biopsy will be obtained at baseline, on cycle 2 day 1, and at the time of surgery if residual tumor. The goal is for 2-4 core biopsy specimens obtained using standard institutional guidelines for a diagnostic core biopsy of a breast mass. However, biopsy samples will preferably be obtained using a 14-18 gauge core needle. At least one core will be use to prepare a paraffin block (paraffin-embedded blocks or formalin fixed tissue) and at least one core will be immediately freeze (snap frozen individually for gene expression). Snap frozen research biopsies will be sent to UAB Tissue Procurement where biopsies will be stored for batching. The batched biopsies will then be forwarded to HudsonAlpha Institute for Biotechnology. All samples will be indelibly labeled with the appropriate study number, and date of  
acquisition; these data will be correlated with clinical efficacy including complete response and objective response. All samples sent to HudsonAlpha Institute for Biotechnology for comprehensive genomic analysis will be labeled with the appropriate study number only. Frozen research biopsy will be used for comprehensive genomic analysis such as Next-GEN genomic analysis. "Next-GEN
genomic analysis will be done at HudsonAlpha Institute for Biotechnology in Huntsville, Alabama
(Shared Facility of the UAB Comprehensive Cancer Center) by Dr. Richard Myers' group. No funding is necessary to conduct the evaluation in the laboratory at this time or macro-dissection; funds are needed only for shipping. Researchers at HudsonAlpha Institute for Biotechnology led by Dr. Richard M. Myers will obtain tissues from Drs. Erica M. Stringer- Reasor and Christos Vaklavas at UAB from patients enrolled in the pilot Study. HudsonAlpha Institute for Biotechnology will analyze the tissues for several functional genomics features on a genome-wide scale, as well as whole exome DNA sequencing, to identify genetic variants. The functional genomics readout and genetic variation measurements will be assessed to help identify differences associated subtypes and/or responses to drug treatments. The researchers at Hudson will utilize their expertise in applying six different genome-wide functional genomics measurements, as well as whole exome sequencing, whole genome sequencing and specialized array-based genotyping to measure genomic and genetic variants for cancers, brain diseases, autoimmune diseases and drug responses. The functional genomics measurements will include the use of ultrahigh throughput sequencing to measure mRNAs and long non-coding RNAs (RNA-seq), microRNAs (miRNA-seq), DNA methylation (a combination of two approaches, RRBS and Methyl1450 arrays), protein:DNA interations (ChIP-seq), chromatin markers (also ChIP-seq) and chromatin accessibility measurements (DNase-seq). To measure DNA sequence variation, two types of ultrahigh throughput DNA sequencing will be performed: whole exome sequencing, where all the exons and exon:intron boundaries in the human genome are sequenced deeply; and whole genome sequencing, to be used on a modest number of samples due to expense. A combination of exome and whole genome sequencing with inexpensive genotyping of 1 million or more polymorphic DNA markers around the genome may be used to supplement the DNA sequencing and to improve the ability to identify large DNA sequence variants known as copy number variants.  
Fifteen slides will be prepared from the paraffin blocks or formalin fixed tissue by Dr. Grizzle at UAB for analysis by conventional IHC of ER, PR, Her-2, EGFR, Ki67, apoptotic markers, and biomarkers of DNA repair such as H2AX and BRCA localization. All samples will be indelibly labeled with the appropriate study number, and date of acquisition; these data will be correlated with clinical efficacy including complete response and objective response. In addition, immunohistochemistry for pAKT and PTEN (markers of the PI3K/AKT/mTOR pathway), CD105 and CD31/CD34 (pan-endothelial markers), and NG2 and MCAM/CD146 (pericyte markers) will be conducted on the diagnostic research tissue, the research biopsy, and the final surgical specimen. Any leftover study blood and tissue samples may be stored for future research studies. The subjects will consent to the future use of samples in the consent form for the study. Any samples will only be released for use in future studies after approval by the Principal Investigator and other regulatory bodies, as appropriate.
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7.3.4 ribosomal profiling on the

Fresh frozen, macrodissected surgical specimens collected and stored in RNA*later* with the assistance of Tissue Procurement that meet criteria for expanded ribosomal profiling will undergo next-generation sequencing. We anticipate that small size of the residual tumor that is surgically excised will be the principal limiting factor in the conduction of this correlative study. Based on our previous experience1,2, we project that in the course of the study approximately 8 surgical specimens will undergo expanded ribosomal profiling. Three samples of previously untreated hormone receptor positive and Her2 negative breast cancer matched for clinical and demographic characteristics with the study samples and 3 samples of normal breast tissue resected for indications other than cancer will undergo expanded ribosomal profiling following the same protocol. Both samples of untreated luminal breast cancer and normal breast tissue will be obtained from patients who will not participate in the study.
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8. assessment of safety 8.1

In the event of an adverse event the first concern will be for the safety of the subject. Toxicities will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (see http://ctep.cancer.gov/reporting/ctc.html - see Appendix D).Adverse events that begin or worsen after informed consent should be recorded. Conditions that were already present at the time of informed consent should be recorded in the Medical History page of the patient's CRF. Adverse event monitoring should be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be described using a diagnosis whenever possible, rather than individual underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be reported as a separate Adverse Event.
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8.1.1 adverse events (aes)

Adverse events should be followed to resolution or stabilization, and reported as SAEs if they become serious. This also applies to patients experiencing AEs that cause interruption or discontinuation of investigational product or those experiencing AEs that are present at the end of their participation in the study. Such patients should receive post-treatment follow-up as appropriate as it has been described throughout the protocol. If an ongoing AE changes in its severity or in its perceived relationship to study drug, a new AE should be completed. The FDA has mandated that Novartis and TRACON be notified, at least one time per year, or at the agreed upon timeframe, of all non-serious adverse events that: (a) are grade 3-4 toxicity and (b) result in the subject's premature discontinuation of the study. In addition, accrual will be halted as a result of "any grade ≥3 hemorrhage, cerebrovascular and vasovagal adverse events; FDA will be contacted to discuss further accrual or potential need for protocol amendment 8.1.2 Serious Adverse Event (SAEs)  
SAEs require expeditious handling and reporting to UAB to comply with regulatory requirements.  
Investigators are required to report within 24 hours of investigator's knowledge (MedWatch Form 3500A) to the principal investigators (UAB - Erica M. Striger- Reasor), who will report to the FDA,
UAB IRB, Novartis, and TRACON in accordance with regulatory requirements or contractual agreement ANY serious treatment emergent (occurring at any time during treatment, not present at baseline and related to study drug) adverse event (SAE) as soon as possible. SAEs must be reported to local IRB according to their institutional guidelines. All SAEs must be collected and reported until 30 days following patient discontinuation of dosing; if only limited information is initially available, follow-up reports are required. The original SAE form must be kept on file at the study site. Any SAEs experienced after this 30 days period should only be reported to Novartis or TRACON pharmaceutical if the investigator suspects a causal relationship to the study drug. Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the original episode within 24 hours of the investigator receiving the follow-up information. A SAE occurring at a different time interval or otherwise considered completely unrelated to a previously reported one should be reported separately as a new event. The end date of the first event must be provided. Follow-up information is sent to the same fax number as the original SAE Report Form was sent, using a new fax cover sheet, stating that this is a follow-up to the previously reported SAE, and giving the date of the original report. Each re-occurrence, complication, or progression of the original event should be reported as a follow-up to that event regardless of when it occurs. The follow-up information should describe whether the event has resolved or continues, if and how it was treated, whether the blind was broken or not (if applicable), and whether the patient continued or withdrew from study participation. A SAE is any sign, symptom or medical condition that emerges during treatment (with everolimus and TRC105) or during a post-treatment follow-up period that (1) was not present at the start of treatment and it is not a chronic condition that is part of the patient's medical history, OR (2) was present at the start of everolimus/TRC105 treatment or as part of the patient's medical history but worsened in severity and/or frequency during therapy, AND that meets any of the following regulatory serious criteria:
Results in death Is life-threatening Requires or prolongs inpatient hospitalization Is disabling Is a congenital anomaly/birth defect Is medically significant or requires medical or surgical intervention to prevent one of the outcomes listed above.  
8.1.3 **Reporting of Serious Treatment Emergent Adverse Events** All SAEs should be recorded on a MedWatch 3500A Form (can be accessed at: https://www.accessdata.fda.gov/scripts/MedWatch - see Appendix E) and faxed to: Pam Dixon Erica M. Sringer- Reasor Phone: 205-975-5387 and Phone: Fax: 205-975-9875 Fax: 205-995-9996 Once forms are reviewed, UAB will report to: And UAB IRB  
| MedWatch                             | Novartis                             |                   |
|--------------------------------------|--------------------------------------|-------------------|
| 5600 Fishers Lane                    | Drug Safety                          |                   |
| Rockville, MD 20852-9787             | and                                  | Fax: 877-778-9739 |
| Fax: 1-800-FDA-0178 (1-800-332-0178) | usdrugsafety.operations@novartis.com |                   |  
and TRACON Drug safety Fax: (XXX) XXX-XXXX XXXX@XXXXXX E-mail: MedWatch 3500A Reporting Guidelines: In addition to completing appropriate patient demographic and suspect medication information, the report should include the following information within the Event Description of the MedWatch 3500A form:
Treatment regimen (dosing frequency, combination therapy)
Protocol description (and number, if assigned)
**Description of event, severity, treatment, and outcome, if known**
Supportive laboratory results and diagnostics Investigator's assessment of the relationship of the adverse event to each investigational product and suspect medication
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follow-up information

Additional information may be added to a **previously submitted report by any of the following** methods:
Adding to the original MedWatch 3500A report and submitting it as follow-up  
Adding supplemental summary information and submitting it as follow-up with the original MedWatch 3500A form Summarizing new information and faxing it with a cover letter including subject identifiers
(i.e. D.O.B., initials, subject number), protocol description and number, if assigned, suspect drug, brief adverse event description, and notation that additional or follow-up information is being submitted (The subject identifiers are important so that the new information is added to the correct initial report)
Occasionally the principal investigator and/or UAB may contact the reporter for additional information, clarification, or current status of the subject for whom an adverse event was reported. Assessing Causality: Investigators are required to assess whether there is a reasonable possibility that everolimus/TRC105 caused or contributed to an adverse event. The following general guidelines may be used. Yes: if the temporal relationship of the clinical event to everolimus/TRC105 administration makes a causal relationship possible, and other drugs, therapeutic interventions or underlying conditions do not provide a sufficient explanation for the observed event. No: if the temporal relationship of the clinical event to everolimus/TRC105 administration makes a causal relationship unlikely, or other drugs, therapeutic interventions or underlying conditions provide a sufficient explanation for the observed event.  
Attribution of the AE:
Definite - The AE *is clearly related* to the study treatment. Probable - The AE *is likely related* to the study treatment. Possible - The AE *may be related* to the study treatment. Unlikely - The AE *is doubtfully related* to the study treatment. Unrelated - The AE *is clearly NOT related* to the study treatment.
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8.2 adverse reactions with everolimus

The most common ADRs (incidence ≥1/10 and suspected to be related to treatment by the investigator) from the pooled safety data were (in decreasing order): stomatitis, rash, fatigue, diarrhea, infections, nausea, decreased appetite, anemia, dysgeusia, pneumonitis, hyperglycemia, weight decreased, pruritus, asthenia peripheral edema, hypercholesterolemia, epistaxis, and headache. The most common grade 3/4 ADRs (incidence ≥1/100 to <1/10 and suspected to be related to treatment by the investigator) were stomatitis, anemia, hyperglycemia, fatigue, infections, pneumonitis, diarrhea, asthenia, thrombocytopenia, neutropenia, dyspnea, lymphopenia, proteinuria, hemorrhage, hypophosphatemia, rash, hypertension, aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, and pneumonia. **Table 8-1** presents the frequency category of ADRs reported in the pooled safety analysis.  
Table 8-1: Adverse Drug Reactions associated with everolimus  
| are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category using the  following convention (CIOMS III) is also provided for each adverse reaction: very common (≥1/10); common (≥1/100 to <1/10);  uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) Infections and infestations Very common Infectionsa Blood and lymphatic system disorders Very common  Common  Uncommon  Rare Anemia,  Thrombocytopenia, neutropenia, leukopenia, lymphopenia Pancytopenia Pure red cell aplasia Immune system disorders Uncommon Hypersensitivity Metabolism and nutrition disorders Very common Decreased appetite, hyperglycemia, hypercholesterolemia Common Hypertriglyceridemia, hypophosphatemia, diabetes mellitus,  hyperlipidemia, hypokalemia, dehydration  Psychiatric disorders Common Insomnia Nervous system disorders Very common Dysgeusia, headache Uncommon Ageusia Cardiac disorders Uncommon Congestive cardiac failure Vascular disorders Common Hemorrhageb, hypertension, Uncommon Deep vein thrombosis Respiratory, thoracic and mediastinal disorders Very common  Common  Uncommon Rare Pneumonitisc, epistaxis,  cough, dyspnea Hemoptysis, pulmonary embolism  acute respiratory distress syndrome Gastrointestinal disorders Very common  Stomatitisd, diarrhea, nausea Common Vomiting, dry mouth, abdominal pain, oral pain, dyspepsia,  dysphagia Skin and subcutaneous tissue disorders Very common Common  Rare Rash, pruritus Dry skin, nail disorder, acne, erythema, hand-foot syndrome Angioedema Musculoskeletal and connective tissue disorders Common Arthralgia Renal and urinary disorders Common Proteinuria, Renal failure Uncommon  Increased daytime urination, acute renal failure Reproductive system and breast disorders Common Menstruation irregularf Uncommon Amenorrhea General disorders and administration site conditions Very common  Common  Uncommon  Rare  Fatigue, asthenia, peripheral edema  Pyrexia, mucosal inflammation Non-cardiac chest pain impaired wound healing Investigations Very common  Weight decreased  Common  aspartate aminotransferase increased, Alanine aminotransferase  increased, blood creatinine increased a Includes all reactions within the 'infections and infestations' system organ class including common: pneumonia96 | P a g e   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
and uncommon: herpes zoster, sepsis and isolated cases of opportunistic infections (e.g. aspergillosis,  
 candidiasis and hepatitis B) b Includes different bleeding events not listed individually c Includes common: pneumonitis: interstitial lung disease, lung infiltration, and rare - alveolitis, pulmonary alveolar hemorrhage, and pulmonary toxicity d Includes very common: stomatitis; common: aphthous stomatitis, mouth and tongue ulceration; uncommon: glossitis, glossodynia e reported as palmar-plantar erythrodysaesthesia syndrome f frequency is based upon number of women age 10 to 55 years of age in the safety pool
table of contents protocol synopsis
8.2.2 clinically relevant laboratory abnormalities

In the pooled double-blind phase III safety database, the following new or worsening clinically relevant laboratory abnormalities were reported with an incidence of ≥1/10 (very common, listed in decreasing frequency).  
Hematology: hemoglobin decreased, lymphocytes decreased, white blood cells decreased, platelets decreased, and neutrophils decreased (or collectively as pancytopenia);
Clinical chemistry: glucose (fasting) increased, cholesterol increased, triglycerides increased, AST increased, phosphate decreased, ALT increased, creatinine increased, and potassium decreased.  
Most of the observed abnormalities (> 1/100) were mild (grade 1) or moderate (grade 2). Grade 3/4 hematology and chemistry abnormalities include:
Hematology: lymphocytes decreased, hemoglobin decreased, (very common); neutrophils decreased, platelet count decreased, white blood cells decreased (all common).  
Clinical chemistry: glucose (fasting) increased, phosphate decreased, potassium decreased, AST
increased, ALT increased, creatinine increased cholesterol (total) increased, triglycerides increased (all common).
table of contents protocol synopsis
8.2.3 serious adverse events associated

Table 8-2 lists all fatal adverse events reported by investigators across all RAD001 studies as having a suspected causal relationship to everolimus and occurring on or before the cut-off date of 31-Mar2014. In clinical trials and post-marketing spontaneous reports, everolimus has been associated with serious cases of the following:
Hepatitis B reactivation, including fatal outcome. Reactivation of infections is an expected event during periods of immunosuppression.  
Renal failure events (including fatal ones) and proteinuria. Monitoring of renal function is recommended.  
Amenorrhea (including secondary amenorrhea).  
Pneumocystis jirovecii pneumonia (PJP) some with a fatal outcome.  
Angioedema has been reported with and without concomitant use of everolimus and ACE
inhibitors Table 8-2  
| MedDRA system organ class                                                 | Event                                                                                                                                                                                                                     |
|---------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Blood and lymphatic system disorders                                      | Thrombocytopenia                                                                                                                                                                                                          |
| Cardiac disorders                                                         | Acute cardiopulmonary event, cardiogenic shock,  cardio-respiratory arrest, myocardial infarction                                                                                                                         |
| Gastrointestinal disorders                                                | Diarrhea, duodenal ulcer, GI hemorrhage, intestinal  perforation, esophageal perforation, internal hernia                                                                                                                 |
| General disorders/administration site conditions                          | Cold sweat, concomitant disease progression, general  physical health deterioration, multi-organ failure,  sudden death                                                                                                   |
| Infections and infestations                                               | Candidal sepsis, EBV pneumonia, neutropenic sepsis,  pneumocystis jiroveci pneumonia, reactivation of  Hepatitis B, septic shock, septicemia with massive  Epstein-Barr viremia                                           |
| Injury, poisoning and procedural complications                            | Bone fissure                                                                                                                                                                                                              |
| Metabolism and nutrition disorders                                        | Dehydration, ketoacidosis, hyperglycemia                                                                                                                                                                                  |
| Neoplasms benign, malignant and unspecified  (including cysts and polyps) | Squamous cell carcinoma of skin                                                                                                                                                                                           |
| Nervous system disorders                                                  | Cerebral hemorrhage, embolic stroke, restlessness                                                                                                                                                                         |
| Renal and urinary disorders                                               | Renal tubular necrosis                                                                                                                                                                                                    |
| Respiratory thoracic and mediastinal disorders                            | Acute cardiopulmonary event, acute respiratory  distress syndrome, cardio-respiratory arrest, dyspnea,  chronic obstructive pulmonary disease, interstitial  pneumonia, pulmonary embolism, pulmonary edema,  pneumonitis |
| Vascular Disorders                                                        | Cerebral hemorrhage, disseminated intravascular  coagulation, embolic stroke, hemorrhage, hypovolemic  shock, myocardial infarction, pulmonary hypertension                                                               |  
Table 8-3 lists all serious, unexpected, life-threatening adverse events considered related to everolimus, and reported on at least one occasion up to the cut-off date of 31-Mar-2014. It should be stressed that many of these SAE reports have been reported only on a single occasion making an accurate assessment of causality difficult, if not impossible. Due to the imprecision of causality, the causality assessments should not be assumed that all of these events are indeed the result of therapy with everolimus. Moreover, the assessment of causality is particularly difficult in critically ill patients where confounding factors are present relating mainly to complications of the underlying disease and to the use of prior therapy and/or concomitant medications. In addition to the SAE reports presented below, disease progression has on occasions been reported somewhat paradoxically as an SAE with a suspected causal relationship to everolimus and reported on at least one occasion. Individual events are presented for each MedDRA system organ class.  
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| MedDRA                         | system                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | organ | Event |
| class                          | Acute leukemia, anemia, bone marrow failure, disseminated intravascular coagulation,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |       |       |
| Blood and lymphatic system     | febrile neutropenia, hemorrhagic diathesis, leukemoid reaction, leukocytosis, leukopenia,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |       |       |
| disorders                      | lymphadenopathy, lymphedema, lymphopenia, neutropenia, pancytopenia, platelet disorder,  retroperitoneal lymphadenopathy, thrombocytopenia, white blood cell disorder, hemolytic  uremic syndrome                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |       |       |
| Cardiac disorders              | atrial fibrillation, atrioventricular block, cardiorespiratory arrest, cardiopulmonary arrest, congestive cardiomyopathy, cyanosis, diastolic dysfunction, dilatation left atrial and  left ventricular, hypertrophy, left ventricular hypertrophy, left ventricular dysfunction,  myocardial infarction, myocardial ischemia, hypertensive heart disease, palpitations, pericardial effusion, right ventricular failure, sinus tachycardia, stress cardiopathy, supraventricular tachycardia, tachycardia, ventricular dysfunction Valve incompetence: mitral/pulmonary/tricuspid                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |       |       |
| Ear and labyrinth disorders    | Vertigo, sudden hearing loss, deafness unilateral                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |       |       |
| Endocrine disorders            | Hyperthyroidism , hyperglycemic non-ketotic syndrome, hypercalcemia, hypothyroidism                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |       |       |
| Eye disorders                  | Conjunctivitis, eyelid edema, scleral discoloration, ocular discomfort, ocular surface disease,  phthalmoplegia_cranial nerve paralysis, papilloedema, photophobia, retinal artery  thrombosis, retinal detachment, retinal hemorrhage, steroid Induced cataract, senile cataract, visual acuity reduced.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |       |       |
| Gastrointestinal disorders     | Abdominal abscess, abdominal adhesions, abdominal: discomfort/distension/pain/tenderness, anorectal discomfort, anal fissure, anal fistula,  anastomotic leak, ascites, colitis, constipation, diarrhea, diverticulum, duodenal ulcer, dyspepsia, dysphagia, esophageal perforation, feces discolored, gastric  perforation, gastric ulcer hemorrhage, gastric ulceration, gastrointestinal angiodysplasia, gastrointestinal ischemia, gastrointestinal oedema, gastroenteritis, hemorrhoids,hematemesis, hematochezia, hiccups, ileus, intestinal perforation, melena,  mesenteric vein thrombosis, mouth ulceration, nausea, pancreatitis, proctalgia, proctitis, recall phenomenon radiation enteritis, rectal discharge/hemorrhage,  small intestinal obstruction, stomatitis, swollen tongue, vomiting, oral pain, enterovesical  fistula, radiation esophagitis, necrotizing esophagitis, salivary gland calculus, small bowel  thickness, thickened bowel Wall Gastritis: erosive/ hemorrhagic Lip:  edema/swelling/ulceration Gastrointestinal: disorder/hemorrhage/sounds Mucosal: hemorrhage/inflammation |       |       |
| General disorders and          | Application site erythema, asthenia, bloody discharge, calcinosis, chest discomfort/pain,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |       |       |
| administration site conditions | chills, concomitant disease progression, condition aggravated, crepitations, death,  discomfort, disease progression, drug ineffective, and drug withdrawal syndrome (asthenia  and flushing) edema peripheral, face edema, facial pain, fatigue, feeling of body temperature  change, general physical health deterioration, generalized edema, goiter, granuloma,  hypertrophy, hypothermia, impaired healing, inflammation, influenza like illness, irritability, local swelling, malaise,  mass, multi-organ failure, necrosis, non-cardiac chest pain, pain, performance status decreased, pitting edema, pyrexia, sudden death, swelling, tenderness,  thirst                                                                                                                                                                                                                                                                                                                                                                                                                                                 |       |       |
| Hepatobiliary disorders        | Cholecystitis, cholelithiasis, cholestasis, cytolytic hepatitis, hepatic cirrhosis, hepatic  failure, hepatic function abnormal, hepatic necrosis, hepatorenal failure, hepatitis B and C  reactivation, hepatomegaly, hyperbilirubinemia, jaundice, portal vein thrombosis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |       |       |
| Immune system disorders        | Acute disseminated encephalomyelitis, autoimmune disorder, cytokine release syndrome,  Guillian Barre syndrome, hypersensitivity, immunosuppression, Stevens- Johnson syndrome                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |       |       |
| Infections and infestations    | Abdominal abscess, aspergillosis, bacteremia, bronchitis, bronchitis viral, bronchopneumonia, bronchopulmonary aspergillosis, candida sepsis, candidiasis, cellulitis, citrobacter sepsis, clostridium bacteremia, endocarditis, escherichia bacteremia, folliculitis, gastroenteritis, gastroenteritis norovirus, hepatitis fulminant, herpes zoster, infected lymphocele, klebsiella sepsis, liver abscess, meningitis, herpes, nasopharyngitis, neutropenic sepsis, oral candidiasis, oral fungal infection, perirectal/anal abscess, pharyngitis, pneumococcal sepsis, pseudomonal bacteremia, purulent discharge, pyelonephritis, rectal abscess, respiratory moniliasis, sepsis, sepsis syndrome, septic shock, sinusitis, staphylococcal99 | P a g e                                                                                                                                                                                                                                                                                                                                                         |       |       |  
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|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|
| bacteremia, staphylococcal sepsis, streptococcal bacteremia, tonsillitis, tuberculosis,  urosepsis Infection(s): alpha hemolytic streptococcal/atypical mycobacterial/bacterial/clostridial/enterobacter/enterococcal/epstein-barr virus/ escherichia/escherichia urinary  tract/gastrointestinal/haemophilus/herpesvirus/fungal/general/klebsiella/localized/low er respiratory tract lung/ morganella/pseudomonas/proteus/respiratory tract/skin/streptococcal/staphylococcal/urinary tract/wound/ wound staphylococcal Pneumonia: Pneumocystis jirovecii/general/bacterial/ streptococcal |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |               |
| Injury, poisoning and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Abdominal adhesion, anastomotic leak, bone fissure, collapse of lung, contusion,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |               |
| Procedural complications                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | eschar, fall, head injury, lung injury, medical device complication, medication error, post procedural swelling, recall phenomenon radiation enteritis, surgical procedure repeated, vena cava injury, wound dehiscence/secretion                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |               |
| Investigations                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Aspiration pleural cavity, antinuclear antibody positive, bleeding time prolonged, breath sounds abnormal, cardiac function test abnormal, chest X-ray abnormal, clostridium difficile toxin test positive, computerised tomogram abnormal, ejection fraction decreased, endoscopy upper gastrointestinal tract, general physical condition abnormal, granulocyte count decreased, hematocrit/hemoglobin decreased, hypophosphatemia, liver function test abnormal, neutrophil count abnormal/decreased, occult blood positive, oxygen saturation abnormal/decreased, peak expiratory flow rate decreased, protein urine present, QRS axis abnormal, urine output decreased, X-ray abnormal; Increased: alanine aminotransferase, ammonia,  aspartate aminotransferase, aspartate aminotransferase, body temperature, C-reactive protein,  eosinophil count, gamma-glutamyltransferase, international normalised ratio, lipase, red  blood cell count, sedimentation rate, transaminases, troponin T, troponin Platelet count:  abnormal/decreased/increased White blood cell(s): count abnormal/decreased/in urine Lymphocyte count:  decreased/increased Blood: amylase increased/albumin decreased/alkaline phosphatase  increased/bilirubin increased/creatine phosphokinase increased/creatinine  increased/magnesium decreased/glucose increased/lactate dehydrogenase  increased/potassium decreased/pressure diastolic decreased/pressure orthostatic  abnormal/pressure systolic decreased/triglycerides increased/urea increased/urine present  Electrocardiogram: T wave abnormal/T wave amplitude decreased/poor R-wave progression  Weight: decreased/ increased |               |
| Metabolism and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Acidosis, anorexia, appetite disorder, cachexia, cushing's syndrome, decreased                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |               |
| nutrition disorders                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | appetite, dehydration, diabetes mellitus, diabetic ketoacidosis, electrolyte imbalance, failure  to thrive, fluid overload/retention, food intolerance, glucose tolerance impaired, gout,  hypothyroidism, malnutrition, metabolic acidosis, oral intake reduced, polydipsia, type 2  diabetes mellitus Hyper: cholesterolemia/glycemia/kalemia/lipidemia/calcaemia uricemia/ triglyceridemia, glycemic non-ketotic syndrome Hypo: calcemia/glycemia/kalemia/magnesemia/natremia/ proteinemia/ Hypophosphatemia                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |               |
| Musculoskeletal and                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Arthritis, bone fissure, fistula, gout mobility decreased, joint effusion, rhabdomyolysis Pain:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |               |
| connective tissue disorders                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | back/flank/musculoskeletal/musculoskeletal chest/extremity/neck Muscle: spasms/weakness;  myalgia, arthralgia Osteoarthritis; Osteonecrosis, Osteoreadionecrosis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |               |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Acute leukaemia, adenocarcinoma of pancreas, Burkitt's lymphoma, carcinoid syndrome, colon neoplasm, lung neoplasm, lymphoproliferative disorder, malignant neoplasm progression, malignant melanoma, malignant pleural effusion, pancreatic carcinoma, squamous cell carcinoma of skin, uterine leiomyoma Metastases: central nervous system/lung/lymph nodes/neoplasm; Tumor: hemorrhage/necrosis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |               |
| Nervous system                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Acute disseminated encephalomyelitis, asterixis, ataxia, cerebrovascular accident,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |               |
| disorders                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | cognitive disorder, complex partial seizures, complex regional pain syndrome, convulsion, depressed level of consciousness, dizziness, dyslalia, encephalitis, encephalopathy, facial palsy, headache, hemiparesis, hemiplegia, hyperglycemic non-ketotic syndrome, hypersomnia, hypoglycemic coma, lethargy, loss of consciousness, ophthalmoplegia_cranial nerve paralysis, neuralgia, neuropathy peripheral,  presyncope, sinus headache, somnolence, speech disorder, tremor, vertigo Cerebral: hemorrhage/ infarction/ischemia; transient ischemic attack                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |               |
| Psychiatric disorders                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Agitated depression, anxiety, confusional state, delirium, delusional disorder,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | 100 | P a g e |  
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| disorientation, drug withdrawal syndrome, libido decreased insomnia, mental disorder/status changes, mood altered, persecutory type, personality disorder, neurosis, staring |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| Renal and urinary                                                                                                                                                            | Acute renal failure, anuria, bladder tamponade, dysuria, hematuria, hemolytic uremic                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| disorders                                                                                                                                                                    | syndrome, hydronephrosis, leukocyturia, nephrolithiasis, oliguria, pollakiuria, polyuria, postrenal failure, renal failure/acute/impairment, urinary bladder hemorrhage, urinary incontinence, renal atrophy, renal colic, renal tubular necrosis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| Reproductive/breast                                                                                                                                                          | Azospermia, endometrial hyperplasia, libido decreased, menorrhagia, pelvic pain, ovarian                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| disorders                                                                                                                                                                    | cyst, scrotal edema                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| Respiratory, thoracic and                                                                                                                                                    | Alveolitis, alveolitis allergic, asthma, atelectasis, bronchomalacia, bronchospasm,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| mediastinal disorders                                                                                                                                                        | cough, cryptogenic organizing pneumonia, diffuse alveolar damage, dysphonia, dyspnea/dyspnea exertional, emphysema, epistaxis, hemoptysis, hydrothorax, hypercapnia, hypoxia, laryngeal edema, interstitial lung disease, laryngeal inflammation, pneumothorax, rales, sinus congestion, stridor, tachypnea, wheezing Acute: respiratory distress syndrome/respiratory failure Lung: consolidation/disorder/infiltration, obstructive airways disorder, orthopnoea, pharyngolaryngeal pain, pleural disorder/effusion/pleurisy/pain; pneumonia aspiration, pneumonitis, pneumothorax, productive cough, rhinorrhoea Pulmonary: congestion/alveolar/hemorrhage/artery dilatation/cavitation/embolism/fibrosis/haemorrhage/hypertension/edema/toxicity Respiratory: arrest/disorder/distress/failure/gas exchange disorder |
| Skin and subcutaneous tissue                                                                                                                                                 | Acute febrile neutrophilic dermatosis, Angioedema, blister, dermatitis, dermatitis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| disorders                                                                                                                                                                    | acneiform, erythema, hyperhidrosis, leukocytoclastic vasculitis, night sweats, petechiae, photosensitivity reaction, pruritus, Stevens-Johnson syndrome Rash: erythematous/generalized/ maculo-papular/pruritic/skin disorder/exfoliation/lesion/reaction/ulcer/palmar plantar erythrodysesthesia/hand foot  syndrome                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Surgical and medical                                                                                                                                                         | Abscess drainage, biliary drainage, bladder irrigation, catheter removal, chest tube                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| procedures                                                                                                                                                                   | insertion, cholecystectomy, debridement, endotracheal intubation, fistula repair, gastric ulcer surgery, gastrointestinal tube insertion, ileojejunal bypass, incisional drainage, laparotomy, mechanical ventilation, pleurodesis, sinus operation, surgery, thoracic cavity drainage, tracheostomy Pericardial: drainage/excision/operation Wound: closure/drainage/treatment                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| Vascular disorders                                                                                                                                                           | Capillary leak syndrome, circulatory collapse, embolism, flushing, gastrointestinal angiodysplasia, gastrointestinal ischaemia, haemorrhoids, hematoma, hemodynamic  instability, hemorrhage, hypertension, hypertensive angiopathy, hypertensive crisis,  hypotension, lymphangiopathy, lymphedema, pallor, shock; transient ischemic attack, retinal  haemorrhage, Thrombosis: deep vein/jugular vein                                                                                                                                                                                                                                                                                                                                                                                                                  |
| *New events added to IB Editions 12 and 13 are noted in bold                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
table of contents protocol synopsis
8.3 adverse reactions with trc105

The most common adverse events associated with TRC105 are infusion reactions that are successfully mitigated with premedications and prolongation of the infusion time, hemorrhages (mostly grade 1 and 2), headaches, and hypoproliferative anemia.
table of contents protocol synopsis
8.3.1 hypoproliferative anemia

TRC105 was administered to 50 patients as part of a phase 1 first-in-human study of solid tumors. Dose escalation proceeded stepwise, and the majority of adverse events were grade 1 or 2. The MTD was 10 mg/kg weekly, and 15 mg/kg every two weeks was also well tolerated. At 15 mg/kg weekly, all 3 patients that remained on study through cycle 2 developed dose-limiting grade 3 anemia, and one of the three progressed to grade 4 anemia by cycle 3. In all three patients, the anemia resolved following discontinuation of treatment. Anemia has been observed in other trials of TRC105. The dose-limiting anemia at 15 mg/kg weekly was associated with accumulation of TRC105 and characterized by a low reticulocyte production index. Additional laboratory and clinical evaluations excluded common causes of anemia including blood loss, hemolysis, plasma volume expansion, inadequate erythropoietin, iron deficiency, and vitamin B-12 or folate deficiency. Bone marrow aspiration attempts in the patient with grade 4 anemia yielded insufficient material to permit evaluation of the cause of anemia. The hypoproliferative anemia was believed to result from TRC105-mediated suppression of proerythroblasts, the only cells in the marrow known to express substantial levels of CD105. Anemia was manageable with standard supportive measures including erythropoietin and packed red blood cell transfusion. One patient dosed in study 105ST101 required dose reduction from 10 mg/kg to 7.5 mg/kg weekly for grade 3 anemia at month 12 and further dose reduced to 6 mg/kg and continued treatment with a minor radiographic response for 20 months. All patients receiving TRC105 should be monitored for anemia and treated appropriately (including possible TRC105 dose reduction).
table of contents protocol synopsis
8.3.2. infusion reactions

Infusion reactions were observed following TRC105 administration, usually with the initial dose, and included one or more of the following signs or symptoms: rigors, bronchospasm, urticaria, change in blood pressure, and change in heart rate. Grade 2 infusion reactions (requiring temporary interruption of the infusion) and grade 3 infusion reactions (requiring discontinuation of the infusion) were initially reported at the 0.3 and 1 mg/kg every 2 weeks in the absence of premedication. By extending the duration of the initial infusion from one to four hours and adding a dexamethasonebased premedication regimen prior to each dose, the frequency and severity of infusion reactions were reduced and dose escalation continued to 15 mg/kg weekly. Infusion reactions were rare in patients re-dosed at the recommended phase 2 dose of 10 mg/kg weekly or 15 mg/kg every two weeks, where TRC105 serum levels known to saturate CD105 binding sites were present at the time of re-dosing. At dose levels where continuous TRC105 serum levels were achieved, dexamethasone was safely discontinued and the infusion duration reduced to one hour. All patients treated with TRC105 should receive appropriate premedication, be monitored during the TRC105 infusion, and be treated appropriately for infusion reactions (including possible TRC105 dose interruption). In a phase 2 study of TRC105 monotherapy in patients with hepatocellular carcinoma who progressed on sorafenib, one patient with coronary artery disease and prior bypass surgery dosed at 15 mg/kg TRC105 who received the required pre-medications, experienced an infusion reaction (Grade 3) with elevated heart rate, elevated blood pressure, shortness of breath and chest pain, and developed a nonQ wave myocardial infarction, from which he recovered without sequellae.  
One patient participating in a phase 1/2 study of TRC105 for castrate-resistant prostate cancer in a NCI sponsored trial developed a serious adverse event of grade 4 vasovagal reaction. The patient was being treated with TRC105 at 15 mg/kg every 2 weeks and, after the appropriate premedication regimen, the patient fainted 17 mL into the initial infusion. He was treated with oxygen and i.v. fluids and completely recovered within 5 minutes. Vasovagal reaction, generally associated with volume 102 depletion, is a known adverse event that occurs in <1% of patients receiving therapeutic proteins like monoclonal antibodies. The risk of syncope can be minimized by encouraging patient hydration prior to the initial treatment with TRC105 and avoiding the treatment of patients who are volume depleted. Hypersensitivity reactions to therapeutic protein infusions are a potential risk for sensitized patients, and TRC105 should be avoided or used with caution in patients with known hypersensitivity to any component of the drug product.