ER/PR+

Courtney Frederick, Tel: 203-737-7992; Fax: 203-785-4069 e-mail:courtney.frederick@yale.edu

OR

Noelle Sowers Office Ph: 203-737-3472, Fax: 203-785-4069 , e-mail: noelle.sowers@yale.edu

Arm A: Doxorubicin (60 mg/m2), Cyclophosphamide (600 mg/m2) ("AC") q 2-3 wk x 4

OR

Arm B: Cisplatin (75mg/m2) q 3 wk x 4 followed by surgery and adjuvant treatment . Surgery no later than 42 days after the last dose of AC or cisplatin. Post-surgical additional chemotherapy will be made by the treating oncologist. However, participants randomized to cisplatin should receive anthracycline-based chemotherapy with or without a taxane after surgery since long-term data using single-agent cisplatin as neoadjuvant treatment of breast cancer is not available.

1. Germline deleterious BRCA mutation. Participants with a BRCA1 or BRCA2 classified as ―variant, suspected deleterious by Myriad Genetics are also eligible for the trial. Participants with only a BRCA1 or BRCA2 VUS (variant of uncertain significance) as classified by Myriad genetics are not eligible for this study.

2. Pathologic confirmation of invasive breast cancer by core biopsy.

3. Clinical T1 ≥ 1.5 cm, T2 or T3, N0-3, M0.

4. ER negative or if it is ER+ it must either be grade 2 or 3 or oncotype recurrence score > 31.

5. Cardiac ejection fraction (LVEF) > institutional lower limit of normal by MUGA/RVG or ECHO

6.Women or men > 18 years of age

7. ECOG performance status <1

8. Lab evaluation: • ANC > 1,500 / mm3 • Platelet count > 100,000/ mm3• Bilirubin < 1.5 x upper limit of normal (ULN) • ALT, AST, ALK Phos < 2.5 x ULN • Creatinine < 1.5 mg/dl or creatinine clearance > 60 cc/min • Glucose < 200 mg/dl • Hemoglobin > 9 mg/dl

9. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy and did not receive prior chemotherapy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.

10. Patient must be willing to undergo research biopsy which is required and mandatory.

1. Any prior chemotherapy at any time.

2. Any prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation or experimental therapy.

3. Ipsilateral breast recurrence, unless prior DCIS.

4. Peripheral neuropathy of any etiology that exceeds grade 1.

5. Significant hearing loss that would prevent cisplatin administration.

6. Renal dysfunction for which exposure to cisplatin would be unsafe or require cisplatin dose modification (i.e., Cre > 1.5 mg/dl or GFR < 60 cc/min).

7. Use of any other investigational or study agents.

8. Active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, steroid dependent asthma, or psychiatric illness.

9. Any condition that would prohibit administration of corticosteroids.

10. Uncontrolled diabetes (fasting blood sugar > 200)

11. Any pre-existing medical condition that would represent toxicity in excess of grade 1 as measured by CTCAE (NCI Common Toxicity Criteria for Adverse Events version 4.0)

12. Known HIV-positive individuals on combination antiretroviral therapy are ineligible.

Main CAF

Noelle Sowers

Office Ph: 203-737-3472,

Fax: 203-785-4069 ,

e-mail: noelle.sowers@yale.edu

Arm A: Endocrine Tx + Everolimus for 54 weeks

OR

Arm B: Endocrine Tx A Arm B: Endocrine therapy + Placebo for 54 weeks

1. ER or PR positive, HER-2 negative breast cancer.

2. Patients must not have metastatic breast cancer. Multifocal, multicentric, synchoronous bilateral, and primary inflammatory breast cancers are allowed.

3. Patients must be high risk by :

• Completion of adjuvant chemotherapy and pathologically negative lymph nodes, and tumor measuring 2 cm in greatest diameter, and an Oncotype DX Recurrence Score > 25. (NOTE: patients with micrometastases as the only nodal involvement (pN1mi) are eligible and will be categorized as node-negative)
• Completion of adjuvant chemotherapy and pathologically 1-3 positive lymph nodes, and either an Oncotype DX Recurrence Score > 25 (screened via S1007 or otherwise) or tumor tissue (Grade III).
• Completion of adjuvant chemotherapy and 4 or more positive lymph nodes .
• Completion of neoadjuvant chemotherapy and 1 or more positive nodes positive lymph nodes. (NOTE: In lymph node positive groups, at least one metastasis 2.0mm must be present. Patients with micrometastases as the only nodal involvement (pN1mi) are eligible and will be categorized as node-negative)

4. Completed either breast-conserving surgery or total mastectomy, with negative margins and appropriate axillary staging.

5. Patients who had breast-conserving surgery must have completed whole breast radiation.

6. Completion of breast/chest wall and nodal basin radiation therapy before randomization and ALND if 4 positive lymph nodes exist.

7. Registration must be no sooner than 21 days after completion of radiation

8. Patients must have undergone axillary staging by sentinel node biopsy or ANLD. For patients with 1-3 positive lymph nodes, sentinel node biopsy alone is allowed provided that the patient completed either whole breast or chest wall radiation and the primary tumor is < 2 cm. All patients with 4 positive lymph nodes must have completed ALND (with or without prior sentinel node biopsy).

8. Completion of standard neoadjuvant or adjuvant taxane and/or anthracycline based chemotherapy prior to randomization. Chemotherapy should include a minimum of 4 cycles. Patients must be registered within 42 weeks after completion of chemotherapy. Patients may have started endocrine therapy at any time after the diagnosis of the current breast cancer.

9. Patients must have a complete history and physical examination within 28 days prior to registration.

10. Lab evaluation: ANC >/= 1,500/mL, hemoglobin >/= 9 g/dL and a platelet count >/= 100,000/ mL Bilirubin 1.5 mg/dL (or 3.0 mg/dL if due to Gilbert's Syndrome) ALT and AST 1.5 x IULN Alkaline phosphatase 1.5 x IULN serum creatinine level IULN within 28 days prior to registration. fasting cholesterol 300 mg/dl and triglycerides 2.5 x IULN obtained within 28 days prior to registration. HgbA1C <7.0% for diabetics.

11. Performance status of 0-2 by Zubrod criteria

12. HIV positive patients with a baseline CD4 count is > 500 cells/mm3 AND not taking anti-retroviral therapy.

13. Must have pre-treatment blood and tissue specimens submitted for translational medicine.

14. Pts (at NCORP Institutions only) must be offered the opportunity to participate in the S1207-E01 Behavioral and Health Outcomes (BAHO) study.

1. Any treatment with trastuzumab. Concurrent bisphosphonate therapy is allowed.

2. Patients must not have prior treatment with any investigational drug within the preceding 28 days and must not be planning to receive any other investigational drug for the duration of the study.

3. Any Grade III/IV cardiac disease as defined by the NYHA.

4. Uncontrolled diabetes defined as an Hg A1C >7% within 28 days prior to registration.

5 Must not have an organ allograft or history of immune compromise. Must not be receiving chronic systemic treatment with corticosteroids or other immunosuppressive agent. Topical or inhaled corticosteroids are allowed.

6. Any known hepatitis or uncontrolled underlying pulmonary disease.

7. Any gastrointestinal disease that may significantly alter the absorption of an oral drug.

8. Immunization with an attenuated live vaccine (e.g. intranasal influenza, MMR, oral polio, varicella, zoster, yellow fever and BCG vaccines) within 7days prior to registration or while on protocol.

9. Strong CYP3A4 inhibitors, and/or CYP3A4 inducers within 14 days prior to registration or while on protocol treatment, .

10. No other prior malignancy is allowed except for adequately treated basal cell (or squamous cell) skin cancer, in situ cervical cancer or other cancer for which the patient has been disease-free for 5 years.

11. Must not be pregant or nursing. Women/men of reproductive potential must have agreed to use an effective non-hormonal contraceptive method.

Randomized 1:1 to receive either: olaparib 300mg twice daily for 12 months or placebo twice daily for 12 months

1. Patients who do not have deleterious or suspected deleterioud gBRCA1 and/or 2 mutation but only have BRCA1 and/or BRCA2 mutations that are considered to be non-detrimental

2. Previous randomization in the present study

3. Evidence of metastatic breast cancer

4. Exposure to an investigational product within 30 days or five half lives (whichever is longer) prior to randomization

5. Any previous treatment with a PARP inhibitor, including olaparib and/or known hypersnsitivity to any of the excipeints of study treatment

6. Patients with second primary malignancy (except adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, DCIS of the breast, stage 1 grade 1 endometrial carcinoma, other solid tumors and lymphomas without bone marrow involvement diagnosed >=5 years prior to randomization and treated with no evidence of disease recurrence and for whom no more than 1 line of chemotherapy was applied

7. Resting ECG with QTc > 470 msec detected on 2 or more time points within a 24 hour period or family history of long QT syndrome

8 .Patients receiving systemic chemotherapy within 3 weeks prior to randomization

9. Patients receiving adjuvant radiotherapy within 2 weeks prior to randomization

9. Concomitant use of known potent CYP3A4 inhibitors

10. Persistent toxicities (>= CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy

11. Patients with myelodyspastic syndrome/treatment related acute myeloid leukemia

12. Major surgery within 2 weeks prior to randomization, patients must have recovered from any effects of any major surgery

13. Patients considered at poor medical risk due to serious, uncontrolled medical disroder, non-malignant systemic disease or active, uncontrolled infection.

14. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of study medication

15. Pregnant or breastfeeding women

16. Patients with known active Hepatitis B or C or HIV positive

17. Previous allogeneic bone marrow transplant

18. Whole blood transfusions in last 120 days prior to entry to study which may interfere with gBRCA testing

BRCA testing CAF

Main CAF

Consent Addendum

Courtney Frederick, Tel: 203-737-7992; Fax: 203-785-4069 e-mail:courtney.frederick@yale.edu

This study has two study groups.

• Group 1 will get a Health Education program that is designed to give women more information about their breast cancer, as well as general information about their general health. Women who are assigned to this group will receive a subscription to a Health magazine and they will receive mailings twice per year with brochures that provide information about breast cancer and health issues. Women will also receive a study newsletter twice per year, and will be able to take part in webinars or teleconferences twice per year that provide information about new updates in breast cancer. Finally, they will get greeting cards on the anniversary of joining the study, holidays, etc.

• Group 2 will get the Health Education program described above and will also get a 2-year weight loss program. This program will be designed to help women lose about 10% of their starting weight by decreasing the calories they eat and by increasing their exercise. Exercise goals will increase slowly over the study, with an overall goal of getting all women exercising at least 150 minutes per week over time. The weight loss program will be provided through a series of 42 telephone calls over 2 years. Each call will take 20-30 minutes. Each woman will be assigned a health coach who will work with her over the 2-year program. Women will need to track the food they eat and the exercise they do each day, especially in the early stages of the program. This will take approximately 15-20 minutes per day. Coaches will track progress using computer programs to help set goals over the 2-year program. Telephone calls will occur more often at the start of the study and become less frequent over time. Women in the weight loss group will also receive:

o A weight loss workbook (available in print and on line)

o An activity sensor (such as a FitBit) to help keep track of exercise

o A cookbook

o A journal and access to a study website to track diet, weight and exercise

o A scale, food scale and measuring cups (if needed)

o Optional text messages to help women meet exercise and diet goals

o Optional pre-packaged shakes, bars or portion-controlled entrees to replace meals

A computer will by chance assign you to one of study groups described above. This is called randomization. This is done by chance because no one knows if one study group is better or worse than the others.

1. Subjects must have histologically confirmed invasive breast cancer and registration must occur within 12 months after the first histologic diagnosis of invasive breast cancer.

• A core biopsy interpreted as invasive cancer meets this criterion; if no core biopsy is performed, the date of first histologic diagnosis will be the date of first surgical procedure that identifies invasive cancer (biopsy, lumpectomy or mastectomy).

• Neoadjuvant subjects should have no evidence of clinical T4 disease prior to chemotherapy and surgery. See eligible cTNM classifications below.

• Bilateral breast carcinoma is allowed provided diagnoses are synchronous – that is, within 3 months of one another – and at least one of the two breast carcinomas meet

2. Her-2 negative, defined as:

• ISH ratio of < 2.0 (if performed)

• IHC staining of 0-2+ (if performed)

• Deemed to not be a candidate for Her-2 directed therapy

3. Eligible TNM Stages include:

• ER and PR negative (defined as < 1 % staining for ER and PR by IHC) T2 or T3 NO, T0-3 N1-3

• ER and/or PR positive (defined as ≥ 1% staining for ER and/or PR on IHC): T0-3N1-3 or T3N0

The eligibility of neo-adjuvant subjects is assessed on the basis of cTNM. The same eligible TNM combinations apply

4. No history of invasive breast cancer in 5 years prior to study registration other than the current diagnosis (prior DCIS at any time is acceptable).

5. Patients must have had a bilateral mammogram within 12 months prior to registration, unless the initial surgery was a total mastectomy, in which case only a mammogram of the remaining breast is required. (Subjects with bilateral total mastectomies do not require imaging).

6. Investigations, including chest X-ray or CT chest, bone scan (with radiographs of suspicious areas) and abdominal ultrasound or liver scan or CT abdomen have been performed between the first histologic diagnosis and the time of registration as detailed below.

• Chest X-Ray, 2 view (or Chest CT, or PET/CT) is mandatory

• Bone scans (with x-rays of abnormal areas) are required only if ALT, AST or Alkaline Phosphatase is elevated or if there are signs or symptoms of metastatic disease

• Abdominal imaging is required only if ALT, AST or Alkaline Phosphatase is elevated or if there are signs or symptoms of metastatic disease

7. All adjuvant or neoadjuvant chemotherapy (at the discretion of the treating physician) and surgery completed at least 21 days prior to registration. Concomitant radiation, biologic therapy, hormonal therapy, and bisphosphonates are acceptable.

8. Surgical margins must be clear of invasive carcinoma. If there is microscopic residual ductal in situ disease present at lumpectomy or total mastectomy margins, further excision is highly recommended. If further excision is not undertaken, the subject may still be entered on study, provided that in addition to breast or chest wall irradiation, a boost to the tumor bed is delivered. In situ lobular disease at the margin is acceptable.

9. All subjects (both adjuvant and neo-adjuvant) must have sentinel lymph node biopsy and/or axillary lymph node dissection. Sentinel lymph node biopsy alone is allowed in the following instances:

a) Sentinel lymph node biopsy is negative: pN0

b) Sentinel lymph node biopsy is positive for isolated tumor cells only: pN0 (i+) c) Clinically node negative, T1-2 tumors with sentinel lymph node biopsy positive in < 2 lymph nodes without matted nodes and undergoing breast conserving surgery and tangential whole breast irradiation, or undergoing mastectomy and chest wall irradiation.

10. All women who undergo breast conserving therapy must receive concomitant radiotherapy. Radiation after mastectomy is to be administered according to prespecified institutional guidelines. Radiation can be administered either prior to or during protocol treatment.

11. Patients with hormone receptor positive breast cancer as defined above must receive at least 5 years of adjuvant hormonal therapy in the form of tamoxifen or an aromatase inhibitor, alone or in combination with ovarian suppression. (NOTE: for patients with ER and PR staining in less than 5% of cells, hormonal therapy for at least 5 years is strongly recommended but not required). Hormonal therapy can be initiated prior to or during protocol therapy

12. Participants must be women

13. Age ≥ 18 years

14. ECOG Performance Status 0 or 1

15. No history of other malignancy within the past 4 years, except for malignancies with a >95% likelihood of cure (e.g. non-melanoma skin cancer, papillary thyroid cancer, in situ cervical cancer).

16. No diabetes mellitus currently treated with insulin or sulfonylureas.

17. No history of serious digestive and/or absorptive problems, including inflammatory bowel disease and chronic diarrhea that preclude adherence to the study diet.

18. No history of severe cardiovascular, respiratory or musculoskeletal disease or joint problems that preclude moderate physical activity. Examples would include unstable angina, recent myocardial infarction, oxygen-dependent pulmonary disease, and osteoarthritis requiring imminent joint replacement. Moderate arthritis that does not preclude physical activity is not a reason for ineligibility.

19. No prior bariatric surgery or planning to undergo this procedure within the next 2 years after study registration.

20. No comorbid conditions that would cause life expectancy of less than 5 years.

21. No history of psychiatric disorders that would preclude participation in the study intervention (e.g. untreated major depression or psychosis, substance abuse, severe personality disorder) or prevent the patient from giving informed consent.

22. BMI ≥27 kg/m2 documented within 56 days prior to study registration.

23. Self-reported ability to walk at least 2 blocks (at any pace).

24. Not participating in another weight loss, physical activity or dietary intervention clinical trial. Co-enrollment in trials involving pharmacologic therapy is allowed. Participants in both arms are also allowed to pursue weight loss and physical activity programs on their own, as long as these programs are not provided as part of a clinical trial.

25. Able to read and comprehend English.

Eligibility is restricted to individuals who can comprehend and read English given that participation in the study will require the ability to read lifestyle intervention materials and communicate with a coach through 42 phone calls over 2 years. Given the logistical and financial difficulties of supporting the intervention in multiple languages, Alliance A011401 Version Date 04/19/2016 21 participation will be limited to individuals speaking English at this time. The study team plans to make the intervention available in additional languages sometime after study activation. This eligibility criterion will be modified with an amendment at that time.

NA

main CAF

Courtney Frederick, Tel: 203-737-7992; Fax: 203-785-4069 e-mail:courtney.frederick@yale.edu

OR

Noelle Sowers Office Ph: 203-737-3472, Fax: 203-785-4069 , e-mail: noelle.sowers@yale.edu

Phase 2 single agent expansion : Single agent GDC-0032 for patients with PI3K amplfication Cohort G—GDC-0032 9mg po daily x 28 days requires PI3KCA mutation. Cohort J— GDC-0032 + Fulvestrant, 21 days on, 7 days off schedule (20 pts) Cohort K—GDC-0032 + Fulvestrant, 5 days on, 2 days off schedule (20 pts) Cohort L—GCC-0032 + Fulvestrant, 7 days on, 7 days off schedule (20 pts) Stage II—GDC-0032 6mg po daily x 28 days + Fulvestrant 500mg IM Q28D (30 pts w PI3KCA mutation, 30 pts w/o PI3KCA mutation) * No prior fulvestrant * ≤ 1 prior chemotherapy (Second line treatment of metastatic disease)

1. Locally advanced or metastatic solid malignancy are failed to respond to at least one prior regimen and are not candidates for regimens known to provide clinical benefit.

2.Phase I, Stage 2 Cohorts G: Patients with solid malignancy with increased PIK3CA copy number, based on archival or fresh tumor tissue.

3. Phase II: Hormone receptor-positive postmenopausal patients as defined in Stage 2 Cohort F. A minimum of 30 patients are required to have PIK3CA-mutant breast cancer.

4. Phase II: Endocrine therapy (i.e., fulvestrant) is recommended and treatment with cytotoxic chemotherapy is not necessary for patients, at time of entry into the study.

5. ECOG performance status of 0 or 1.

6. Lab evaluation within 14 days prior to initiation of study treatment: • Granulocyte count ≥ 1500/μL, • Hemoglobin ≥ 9 g/dL, • Platelet count ≥ 100,000/μL, • Fasting glucose ≤ 120 mg/dL, • Total bilirubin ≤ 1.5 ×ULN, (Known Gilbert’s disease with serum bilirubin ≤ 3 ×ULN may be enrolled) • Serum albumin ≥ 2.5 g/dL ,• AST, ALT, alkaline phosphatase ≤ 1.5 × ULN except patients with documented liver metastases may have AST and/or ALT ≤ 5.0 × ULN and alkaline phosphatase ≤ 5 ×ULN,• Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min, • INR< 1.5 × ULN and aPTT < 1.5 ×ULN, • For patients requiring anticoagulation therapy with warfarin, a stable INR between 2−3 is required. If anticoagulation is required for a prosthetic heart valve, then INR should be between 2.5−3.5.

7. Willingness to provide archival tumor tissue

1. For patients in Stage 2 (Phase I) and Phase II: prior treatment with PI3-kinase inhibitors

2. For patients in Phase II: prior treatment with fulvestrant

3. For patients in Phase II: Prior treatment with > 1 cytotoxic chemotherapy regimen in the metastatic setting (Prior treatment with everolimus is permitted and is not considered a cytotoxic chemotherapy).

4. Leptomeningeal disease as the only manifestation of the current malignancy

5. Type 1 or 2 diabetes requiring daily anti-hyperglycemic medication

6. Malabsorption syndrome or other condition (such as Crohn’s disease or ulcerative colitis) that would interfere with enteral absorption

7. Known and untreated, or active CNS metastases (progressing or requiring anticonvulsants for symptomatic control). Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria: a. Disease outside the CNS is present, b. No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study, c. No history of intracranial hemorrhage or spinal cord hemorrhage, d. Minimum of 2 weeks between completion of radiotherapy and Cycle 1 Day 1 and recovery from significant (Grade ≥ 3) acute toxicity with no ongoing requirement for ≥ 10 mg of prednisone per day or an equivalent dose of other corticosteroid.

8. Congenital long QT syndrome or QTc > 500 msec, active congestive heart failure or ventricular arrhythmia requiring medication

9. Uncontrolled ascites requiring weekly large-volume paracentesis for 3 consecutive weeks prior to initiation of study treatment

10. Active infection requiring intravenous (IV) antibiotics

11. Patients requiring any daily supplemental oxygen

12. Uncontrolled hypomagnesemia or hypokalemia despite adequate electrolyte supplementation or management. Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab therapy

13. Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis

14. Known HIV infection

15. Significant traumatic injury within 3 weeks prior to initiation of GDC-0032

16. Major surgical procedure within 4 weeks prior to initiation of GDC-0032

17. Treatment with chemotherapy, hormonal therapy (except GnRH agonists or antagonists for prostate cancer), immunotherapy, or biologic therapy as cancer therapy within 3 weeks prior to initiation of study treatment

18. Patients who are receiving letrozole prior to study entry may continue letrozole treatment if they are enrolled to Stage 2 Cohort E.

19. Kinase inhibitors may be used up to 2 weeks prior to initiation of GDC-0032, provided drug-related toxicity has resolved.

20. Prior treatment with a PI3-kinase inhibitor in which the patient experienced a Grade ≥ 3 drug-related adverse event or otherwise would be at increased risk for additional PI3K-related toxicity

21. Palliative radiation to bony metastases within 2 weeks radiation therapy (other than palliative radiation to bony metastases) as cancer therapy within 4 weeks prior to initiation of GDC-0032

22. Treatment with an investigational agent within 4 weeks

Main CAF

Optional

Courtney Frederick

Tel: 203-737-7992

Fax: 203-785-4069

e-mail:courtney.frederick@yale.edu

The trial includes a screening phase with I-124 to identify patients whose cancer enriches iodine. Those who meet enrichment criteria will be treated with a I-131 that is used to treat metastatic thyroid cancer, where it is highly effective. The treatment is a ONE TIME ORAL THERAPY with I-131 capsules AT THE MAIN CAMPUS that are dosed based on the I-124 uptake level.

1. All breast cancer subtypes (TNBC, ER+, HER2+) are eligible but have to have disease progression after treatment with all available therapies known to confer clinical benefit and have.

2. Radiological evidence of measurable or evaluable metastatic disease by Response Evaluation in Solid Tumors (RECIST) 1.1

3. There is no restriction on the number of prior lines of therapy.

4. Less than 70 years of age (patients older than age 70 are at an increased risk of thyrotoxicosis)

5. Eastern Cooperative Oncology Group (ECOG) Performance Status score of < 2.

6. Recovery to Grade ≤ 2 from any prior side effects of prior therapy for cancer.

7. Adequate bone marrow function defined as white blood cells (WBCs) ≥ 3.0 × 109/L, neutrophils ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L. Adequate renal function defined as serum creatinine < 1.5 mg/dL or creatinine clearance (GFR) > 40 mL/min calculated using the following formula: GFR = 175 x Serum Cr-1.154 x age-0.203 x 0.742 (female) and x 1.212 (if patient is African American).

8. Adequate liver function defined as AST, ALT ≤ 3 × upper limit of normal (UNL) in the absence of liver metastasis and ≤ 5 × UNL with liver metastases; bilirubin < 1.5 × UNL; alkaline phosphatase ≤ 2.5 × UNL in the absence of bone metastasis and ≤ 5 × UNL in case of bone metastases.

9. TSH, T3 and free T4 must be within normal range.

10. The patient should not have had intravenous or intrathecal iodinated contrast agents (IVP, CT with contrast, myelogram, and angiogram) for 4 weeks prior to screening 124I- PET/CT scans and/or 131I- treatment.

11. Patients with treated brain metastases are eligible if the brain metastases have remained stable for more than 4 weeks after completing therapy to the brain.

12. Normal urine or serum Beta-HCG in premenopausal women of childbearing potential.

13. Women of childbearing potential must agree to use effective contraception during the treatment period and for at least 6 months after the last dose of 124I- and/or 131I- as these agents interfere with radioactive iodide uptake

1. Concurrent anti-tumor treatment including radiation therapy, hormonal and chemotherapy.

2. Patients with underlying symptomatic cardiac disease such as coronary artery disease, congestive heart failure, or atrial fibrillation.

3. Significant gastrointestinal abnormalities, including: ulcerative colitis, chronic diarrhea associated with intestinal malabsorption, Crohn's disease, and prior surgical procedures affecting absorption.

4. Women who are nursing or pregnant

PhaseI

PhaseII

Noelle Sowers

Office Ph: 203-737-3472

Fax: 203-785-4069 ,

e-mail: noelle.sowers@yale.edu

All patients will receive SGN-LIV1A. Patients enrolled in Part B will receive SGN-LIV1A in combination with trastuzumab. This study will be conducted in 2 parts (Part A: monotherapy, Part B: combination therapy). SGN-LIV1A will be administered on Day 1 of of 3-week cycles as a 30-minute IV infusion. Research biopsy has to be obtained on Cycle 1 Day 5 (window Day 47).

1. Pathologically confirmed diagnosis of breast cancer with radiographic evidence of incurable, unresectable, locally advanced or metastatic disease.

2. Part A: Patients with triple-negative disease must have received at least 2 prior cytotoxic regimens in the incurable, unresectable, LA/MBC setting.

Patients with ER- and/or PR-positive/HER2-negative disease must have received at least 2 prior cytotoxic regimens in the incurable, unresectable, LA/MBC setting, and are no longer a candidate for hormonal therapy.

Part B: Patients with HER2-positive disease must have received at least 2 prior cytotoxic regimens in the incurable, unresectable LA/MBC setting.

HER2-positivity will be determined by the local lab.

3. Positive for LIV-1 expression on newly obtained tumor tissue biopsy. Archived tumor tissue, if available, is also required for LIV-1 expression analysis. 80-90% of patients are expected to be positive.

4. Measureable disease as defined in RECIST Version 1.1: at least 1 tumor lesion 10 mm in the longest diameter or a lymph node 15 mm in short axis measurement assessed by CT scan.

5. Females18 years of age.

6. ECO 0 or 1

7. Patients must have completed treatment with chemotherapy, radiotherapy, hormonal therapy, or other treatment with an investigational agent 2 weeks prior to first dose of study drug, unless disease progression is documented, and have recovered from any clinically significant toxicity associated with the treatment.

8. Patients must have completed treatment with a biologic agent or immunotherapy 4 weeks prior to the first dose of study drug, unless disease progression is documented, and have recovered from any clinically significant toxicity associated with the treatment. An exception to this requirement is treatment with denosumab, which is permitted on study.

9. Lab evaluation: absolute neutrophil count (ANC) 1500/?L, platelet count 100,000/?L, hemoglobin 8.0 g/dL, serum bilirubin 1.5x upper limit of normal (ULN), serum creatinine 1.5x ULN, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 1.5x ULN or 3x ULN if liver metastases present

10. Negative pregnancy test resultand must agree to use 2 effective contraception methods during the study and for an extended time following the last dose of study drug.

11. Part B only: LVEF 50% as determined by echocardioggram or MUGA scan.

1. Pre-existing neuropathy ≥Grade 2.

2. Another primary invasive malignancy that has not been in remission for at least 3 years with the exception of carcinoma in situ of the cervix, squamous or basal cell skin cancer, or thyroid cancer.

3. Cerebral/meningeal disease related to breast cancer and has not been definitively treated.

4. Any active Grade 3 or higher toxicity within 2 weeks prior to the first dose of SGN-LIV1A.

5. Positive HBsAg, active hepatitis C infection, or a known history of being seropositive for HIV.

6. Documented history of a cerebral vascular event, unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association Class III-IV within 6 months prior to their first dose of SGN-LIV1A.

7. Any P-gp inducers/inhibitors or strong CYP3A inducers/inhibitors within 2 weeks prior to the first dose of study drug.

8. Females who are breastfeeding.

9. Known hypersensitivity to any excipient contained in the drug formulation of SGN-LIV1A.

10. Major surgery ≤3 weeks of study treatment.

Part B only: known hypersensitivity to Trastuzumab

Main Consent

Optional Tests Consent

Courtney Frederick,

Tel: 203-737-7992;

Fax: 203-785-4069

email:courtney.frederick@yale.edu

Study Group 1: Radium-223 dichloride at a dose of 55 kBq per kilogram of body weight once every 28 days for a maximum of six injections through the vein, plus exemestane and everolimus therapy as prescribed by your doctor.

Study Group 2: A normal saline dose (placebo) once every 28 days for a maximum of six injections through the vein, plus exemestane and everolimus therapy as prescribed by your doctor.

1. Have provided written informed consent. Subjects must be able to understand and be

willing to sign the written informed consent. A signed ICF must be appropriately

obtained prior to the conduct of any study-specific procedure.

2. Documentation of histological or cytological confirmation of ER+ and HER2 negative adenocarcinoma of the breast must be available. HER2 status should be determined by an accredited/Ministry of Health approved laboratory by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) or other validated in situ hybridization (ISH) assay for detection of HER2 gene expression.

3. Tumors (from either primary or metastatic sites) must be ER+ defined as ≥10% positive tumor nuclei in the analyzed sample. ER+/ progesterone receptor positive (PR+), ER+/ progesterone receptor negative (PR-) subjects are eligible whereas estrogen receptor negative (ER-)/PR+ and ER-/PR- disease will not be eligible.

4. Women (≥18 years of age) with metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy. Women of reproductive potential and their male partners must agree to use adequate contraception during treatment and for 6 months following the completion of treatment with radium-223 dichloride/placebo.

5. Documentation of menopausal status: post-menopausal or pre-menopausal subjects are eligible

• Pre-menopausal subjects with ovarian radiation or concomitant treatment with

an LH-RH agonist/antagonist must have a plasma/serum estradiol assay of

<20 pg/mL at screening within 7 days prior to randomization. These subjects

must also have a negative pregnancy test at screening and agree to use an

adequate method of contraception as recommended by their treating physicians (please refer to Section 8.1.2)

• Post-menopausal status is defined either by

- Age ≥55 years and one year or more of amenorrhea

- Age <55 years and one year or more of amenorrhea with a plasma/serum estradiol assay <20 pg/mL, within 7 days of randomization

- bilateral ovariectomy

6. Subjects with bone dominant disease with at least 2 skeletal metastases identified at baseline by bone scintigraphy and confirmed by CT/magnetic resonance imaging (MRI). Presence of metastases in soft tissue (skin, subcutaneous, muscle, fat, lymph nodes) and/or visceral metastases is allowed.

7. Measurable or non-measurable disease (but radiologically evaluable) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. All disease burden must be assessed at baseline by CT or MRI of chest, pelvis, and abdomen and any additional fields as needed. A bone scan should also be done at baseline for all subjects. CT/MRI done as part of the standard of practice within 3 weeks prior to randomization and standard of care bone scans done within 3 weeks prior to randomization are acceptable. FDG PET scan, if performed as part of standard of care imaging, can be used as an adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT component of the scan can be used for tumor measurements only if the site can document that the CT is of identical diagnostic quality to a diagnostic CT. FDG PET/CT or NaF PET3 /CT scan is acceptable as an alternative to technetium- 99m bone scintigraphy if it is the standard of care at the institution, provided the same bone imaging modality is used throughout the study.

8. Subjects must have experienced recurrent/progressive disease following treatment with a non-steroidal aromatase inhibitor (letrozole or anastrozole) in an adjuvant or metastatic setting.

9. Subjects must have received at least one line of hormonal therapy in the metastatic setting.

Note: A change of the hormone agent due to progression (as per the Investigator assessment) is counted as a new line of therapy. A switch of hormone therapy from one agent to another due to toxicity or other reasons (e.g., subject’s preference), in absence of PD at the time of the switch, will be counted as one line although 2 different agents have been administered.

10. Subjects who are eligible, as per Investigator’s assessment and according to the local label, for treatment with exemestane and everolimus as a second line or greater if hormone therapy in a metastatic setting. Subjects enrolled in the current study will start treatment with exemestane and everolimus after randomization either before or simultaneously to the first injection of radium 223 dichloride/placebo

11. Subjects must have experienced no more than 2 SREs prior to study entry defined as: EBRT for bone pain, pathological bone fracture (excluding major trauma), spinal cord compression, and/or orthopedic surgical procedure. Subjects with no prior SREs are not permitted.

Note: All prior SRE-related procedures (i.e., orthopedic surgery, EBRT) must be administered prior to randomization.2 Separate SRE events are the ones that occur at least 21 days apart from each other to ensure that linked events (eg, surgery to repair a fracture or multiple doses of radiation during a course of treatment) are not counted as separate events. In case of bone pain that occurs in several anatomical locations and requires separate EBRT sessions, it should be counted as one event if the EBRT sessions are administered within a period of 21days

12. Subjects must be on therapy with bisphosphonate or denosumab and are required to have been on such therapy for at least 1 month before the start of study treatment.

13. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

14. Life expectancy ≥6 months

15. Screening for laboratory values within the following parameters

Hemoglobin ≥ 9.0 g/dl

ANC ≥ 1,500/mm3

Platelets ≥ 100,000/mm3

Total Bilirubin ≤ 1.5x ULN (unless evidence of Gilbert’s disease confirmed by uridine diphosphate-glucuronyltransferase [UGT] polymorphism)

AST (SGOT) ≤ 2.5 X ULN (must not be related to liver involvement)

ALT (SGPT) ≤ 2.5 X ULN ( Must not be related to liver involvement)

Serum creatinine ≤1.5x ULN or creatinine clearance > 45ml/min by MDRD

Estimated Glomerular filtration rate ≥ 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD)

INR/ PTT ≤1.5x ULN Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban,dabigatran, apixaban, or aspirin (e.g. ≤100 mg daily) will be allowed to participate in the study if no underlying abnormality in coagulation parameters exists per prior history; weekly evaluation of INR/PTT will be required until stability is achieved for anticoagulants that require their monitoring as per local label

Serum Albumin > 30 g/L

Pulse oximetry 92%

16. Able to swallow oral medication

1. HER2-positive breast cancer (IHC=3+, positive FISH/CISH/other ISH validated assay); equivocal or unknown HER2 status

Note: Subjects with 3+ by IHC cannot be chosen regardless of their FISH/CISH/other ISH validated assay status and those with positive FISH/CISH/other ISH validated assay cannot be chosen either, regardless of the IHC findings. Subjects with 2+ by IHC will not be eligible if no negative FISH/CISH/other ISH validated assay for detection of HER2 gene expression is available

2. Subjects with immediate life-threatening visceral disease, for whom chemotherapy is the preferred treatment option.

3. Lymphangitic carcinomatosis

4. Patients with ascites requiring paracentesis within 2 weeks prior to study entry (signature of informed consent) and during the screening process

5. Subjects with the following cancers:

• Inflammatory Breast Cancer

• Bilateral breast cancer or a history of 2 distinct breast cancers

6. Subjects who have either received chemotherapy for metastatic disease or are considered by the treating Investigator to be appropriate candidates for chemotherapy as current treatment for metastatic breast cancer are excluded. Chemotherapy administered for adjuvant/ neoadjuvant disease is acceptable provided it was administered at least 1 year prior to study entry.

7. Subjects with any previous untreated or concurrent cancer that is distinct in primary site or histology from the cancer under study, except treated basal cell carcinoma or superficial bladder tumor (Ta and Tis, American Joint Committee on Cancer, 7th edition). Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before enrollment are allowed. All cancer treatments must be completed at least 3 years prior to study entry (i.e. signature date of ICF).

8. Subjects with known or history of brain metastases or leptomenigeal disease: subjects with neurological symptoms must undergo a contrast CT scan or MRI of brain within 28 days prior to randomization to exclude active brain metastasis. Imaging of the central nervous system is otherwise not required.

9. Imminent or established untreated spinal cord compression based on clinical findings and/or MRI. Following treatment of spinal cord compression, the subject may be eligible if all other eligibility criteria are fulfilled.

10. Prior treatment with radium-223 dichloride

11. Prior hemibody external radiotherapy. Subjects who received other types of prior external radiotherapy are allowed provided that bone marrow function is assessed and meets the protocol requirements for hemoglobin, ANC and platelets.

12. Prior systemic radiotherapy with strontium-89, samarium-153, thenium-186, or rhenium-188

13. ECOG Performance Status ≥ 2

14. Blood transfusions, platelet transfusions or use of erythropoietin within 4 weeks prior to randomization.

15. Use of biologic response modifiers, such as granulocyte macrophage colony stimulating factor (GM-CSF) or granulocyte colony-stimulating factory (G-CSF), within 4 weeks prior to randomization

16. Treatment with an investigational drug or with any anti-cancer treatments not permitted by the protocol, within 4 weeks prior to randomization.

17. Chronic conditions associated with non-malignant abnormal bone growth (e.g. confirmed Paget’s disease of bone)

18. Any other serious illness or medical condition such as, but not limited to:

• Any uncontrolled infection

• Cardiac failure New York Heart Association Class III or IV

• Crohn’s disease or ulcerative colitis

• Bone marrow dysplasia

19. Previous assignment to treatment in this study

20. Breastfeeding women

21. Known hypersensitivity to the active substance or any of the excipients of radium-223 dicholoride

22. Subjects who received prior treatment or are already receiving everolimus treatment prior to study entry are not eligible.

23. Known presence of osteonecrosis of jaw.

Main CAF

Courtney Frederick,

Tel: 203-737-7992;

Fax: 203-785-4069

email:courtney.frederick@yale.edu

Study Group 1: Radium-223 dichloride at a dose of 55 kBq per kilogram of body weight once every 28 days for a maximum of six injections through the vein, plus the standard of care hormonal therapy and best supportive care as prescribed by your doctor.

Study Group 2: A normal saline dose (placebo) once every 28 days for a maximum of six injections through the vein, plus the standard of care hormonal therapy and best supportive care as prescribed by your doctor.

1. Have provided written informed consent. Subjects must be able to understand and be

willing to sign the written informed consent. A signed ICF must be appropriately

obtained prior to the conduct of any study-specific procedure.

2. Documentation of histological or cytological confirmation of ER+ and HER2 negative adenocarcinoma of the breast must be available. HER2 status should be determined by an accredited/Ministry of Health approved laboratory by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) or other validated in situ hybridization (ISH) assay for detection of HER2 gene expression. 1

3. Tumors (from either primary or metastatic sites) must be ER+ defined as ≥10% positive tumor nuclei in the analyzed sample. ER+/ progesterone receptor positive (PR+), ER+/ progesterone receptor negative (PR-) subjects are eligible whereas estrogen receptor negative (ER-)/PR+ and ER-/PR- disease will not be eligible.

4. Women (≥18 years of age) with metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy. Women of reproductive potential and their male partners must agree to use adequate contraception during treatment and for 6 months following the completion of treatment with radium-223 dichloride/placebo.

5. Documentation of menopausal status: post-menopausal or pre-menopausal subjects are eligible.

Note: In premenopausal subjects, ovarian radiation or treatment with an LH-RH agonist/antagonist is permitted for induction of ovarian suppression if the plasma/serum estradiol assay is < 20 pg/mL at screening, within 7 days of randomization.

• Pre-menopausal subjects with or without ovarian radiation or concomitant treatment with an LH-RH agonist/antagonist must have a negative pregnancy test at screening and agree to use an adequate method of contraception as recommended by their treating physicians (please refer to Section 8.1.2)

• Post-menopausal status is defined either by

- Age ≥55 years and one year or more of amenorrhea

- Age <55 years and one year or more of amenorrhea with a

plasma/serum estradiol assay <20 pg/mL, within 7 days of

randomization

- bilateral ovariectomy

6. Subjects with bone dominant disease with at least 2 skeletal metastases identified at baseline by bone scintigraphy and confirmed by CT/magnetic resonance imaging (MRI). Presence of metastases in soft tissue (skin, subcutaneous, muscle, fat, lymph nodes) is allowed.

7. Measurable or non-measurable disease (but radiologically evaluable) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. All disease burden must be assessed at baseline by CT or MRI of chest, pelvis, and abdomen and any additional fields as needed. A bone scan should also be done at baseline for all subjects. CT/MRI done as part of the standard of practice within 3 weeks prior to randomization and standard of care bone scans done within 3 weeks prior to randomization are acceptable. FDG PET scan, if performed as part of standard of care imaging, can be used as an adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT component of the scan can be used for tumor measurements only if the site can document that the CT is of identical diagnostic quality to a diagnostic CT. FDG PET/CT or NaF PET3 /CT scan is acceptable as an alternative to technetium- 99m bone scintigraphy if it is the standard of care at the institution, provided the same bone imaging modality is used throughout the study.

8. Subjects must have received at least one line of hormonal therapy in the metastatic setting.

Note: A change of the hormone agent due to progression (as per the Investigator assessment) is counted as a new line of therapy. A switch of hormone therapy from one agent to another due to toxicity or other reasons (e.g., subject’s preference), in absence of PD at the time of the switch, will be counted as one line although 2 different agents have been administered.

9. Subjects who are eligible for further standard of care endocrine treatment with any of the following administered as in second line or greater of hormone therapy in metastatic setting:

• SERMs such as tamoxifen and toremifene

• NSAIs such as anastrozole and letrozole

• Steroidal AIs such as exemestane

• ER down-regulators such as fulvestrant

10. Subjects must have experienced no more than 2 SREs prior to study entry defined as: EBRT for bone pain, pathological bone fracture (excluding major trauma), spinal cord compression, and/or orthopedic surgical procedure. Subjects with no prior SREs are not permitted.

Note: All prior SRE-related procedures (i.e., orthopedic surgery, EBRT) must be administered prior to randomization.2 Separate SRE events are the ones that occur at least 21 days apart from each other to ensure that linked events (eg, surgery to repair a fracture or multiple doses of radiation during a course of treatment) are not counted as separate events. In case of bone pain that occurs in several anatomical locations and requires separate EBRT sessions, it should be counted as one event if the EBRT sessions are administered within a period of 21days

11. Subjects must be on therapy with bisphosphonate or denosumab and are required to have been on such therapy for at least 1 month before the start of study treatment.

12. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1

13. Life expectancy ≥6 months

14. Screening for laboratory values within the following parameters

Hemoglobin ≥ 9.0 g/dl

ANC ≥ 1,500/mm3

Platelets ≥ 100,000/mm3

Total Bilirubin ≤ 1.5x ULN (unless evidence of Gilbert’s disease confirmed by uridine diphosphate-glucuronyltransferase [UGT] polymorphism)

AST (SGOT) ≤ 2.5 X ULN (must not be related to liver involvement)

ALT (SGPT) ≤ 2.5 X ULN ( Must not be related to liver involvement)

Serum creatinine ≤1.5x ULN or creatinine clearance > 45ml/min by MDRD

Estimated Glomerular filtration rate ≥ 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD)

INR/ PTT ≤1.5x ULN Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban,dabigatran, apixaban, or aspirin (e.g. ≤100 mg daily) will be allowed to participate in the study if no underlying abnormality in coagulation parameters exists per prior history; weekly evaluation of INR/PTT will be required until stability is achieved for anticoagulants that require their monitoring as per local label

Serum Albumin > 30 g/L

15. Able to swallow oral medication

1. HER2-positive breast cancer (IHC=3+, positive FISH/CISH/other ISH validated assay); equivocal or unknown HER2 status

Note: Subjects with 3+ by IHC cannot be chosen regardless of their FISH/CISH/other ISH validated assay status and those with positive FISH/CISH/other ISH validated assay cannot be chosen either, regardless of the IHC findings. Subjects with 2+ by IHC will not be eligible if no negative FISH/CISH/other ISH validated assay for detection of HER2 gene expression is available

2. Subjects considered by treating investigator to be appropriate candidates for treatment with everolimus as current treatment for their metastatic breast cancer

3. Subjects with the following cancers:

• Inflammatory Breast Cancer

4. History and/ or presences of confirmed visceral metastases

5. Subjects who have either received chemotherapy for metastatic disease or are considered by the treating Investigator to be appropriate candidates for chemotherapy as current treatment for metastatic breast cancer are excluded. Chemotherapy administered for adjuvant/neo-adjuvant disease is acceptable

provided it was administered at least 1 year prior to study entry.

6. Subjects with any previous untreated or concurrent cancer that is distinct in primary site or histology from the cancer under study, except treated basal cell carcinoma or superficial bladder tumor (Ta and Tis, American Joint Committee on Cancer, 7th edition). Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before enrollment are allowed. All cancer treatments must be completed at least 3 years prior to study entry (i.e. signature date of ICF).

7. Subjects with known or history of brain metastases or leptomenigeal disease: subjects with neurological symptoms must undergo a contrast CT scan or MRI of brain within 28 days prior to randomization to exclude active brain metastasis. Imaging of the central nervous system is otherwise not required.

8. Imminent or established untreated spinal cord compression based on clinical findings and/or MRI. Following treatment of spinal cord compression, the subject may be eligible if all other eligibility criteria are fulfilled.

9. Prior treatment with radium-223 dichloride

10. Prior hemibody external radiotherapy. Subjects who received other types of prior external radiotherapy are allowed provided that bone marrow function is assessed and meets the protocol requirements for hemoglobin, ANC and platelets.

11. Prior systemic radiotherapy with strontium-89, samarium-153, thenium-186, or rhenium-188

12. ECOG Performance Status ≥ 2

13. Blood transfusions, platelet transfusions or use of erythropoietin within 4 weeks prior to randomization.

14. Use of biologic response modifiers, such as granulocyte macrophage colony stimulating factor (GM-CSF) or granulocyte-colony stimulating factor (G-CSF) within 4 weeks prior to randomization

15. Treatment with an investigational drug or with any anti-cancer treatments not permitted by the protocol, within 4 weeks prior to randomization.

16. Chronic conditions associated with non-malignant abnormal bone growth (e.g. confirmed Paget’s disease of bone)

17. Any other serious illness or medical condition such as, but not limited to:

• Any uncontrolled infection

• Cardiac failure New York Heart Association Class III or IV

• Crohn’s disease or ulcerative colitis

• Bone marrow dysplasia

18. Previous assignment to treatment in this study

19. Breastfeeding women

20. Known hypersensitivity to the active substance or any of the excipients of radium-223 dicholoride

21. Known presence of osteonecrosis of jaw.

Main CAF