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TNBC

Neoadjuvant

Randomized phase II trial of neoadjuvant Cisplatin vs. Doxorubicin/Cyclophosphamide (“AC”) in women with newly diagnosed breast cancer and germline brca mutations (Inform Study)
Contact Treatment Inclusion Criteria Exclusion Criteria Informed Consent

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

HIC:1305012020CA

Single Arm Neoadjuvant Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) Concomitant with Weekly Nab-paclitaxel and Dose Dense Doxorubicin/Cyclophosphamide (AC) Chemotherapy for Clinical Stage I-III Triple Negative Breast Cancer
Contact Treatment Inclusion Criteria Exclusion Criteria InformedConsent

Courtney Frederick,

Tel: 203-737-7992;

Fax: 203-785-4069

email:

courtney.frederick@yale.edu


The first 3 subjects treated on this study will receive MEDI4736 at a dose level of 3 mg per kilogram body weight, in combination with the standard of care chemotherapy. If there is no significant concern for side effects at this dose, the dose of MEDI4736 will be increased to 10 mg per kilogram for all subsequent subjects.


The safety and effectiveness of the study drug will also be assessed after the first 22 subjects have completed therapy, if there are no serious safety concerns and there is no indication that the effectiveness of therapy is low, the study will enroll a maximum of 61 subjects.


All subjects will receive chemotherapy treatment which is standard of care. You will also be given anti-nausea medications and additional medicines to reduce the risk of allergic reactions to drugs before each chemotherapy. The duration of each treatment session lasts between 1.5 – 4.0 hours. All drugs in this study are given through a needle in your vein (intravenously). You will need to have a central venous access, a catheter or port inserted in a large vein, in order to receive therapy. You and your physician will decide together what catheter is most convenient for you.


The total duration of treatment is 20 weeks. During the first 12 weeks (weeks 1-12) you will receive Nab-paclitaxel (also called Abraxane) chemotherapy once a week for 12 treatments concomitant with every other week MEDI4736 (weeks 1, 3, 5, 7, 9, 11) on the same days as the Nab-paclitaxel.


After completion of the Nab-paclitaxel phase of the therapy, you will receive doxorubicin (also called Adriamycin) and cyclophosphamide (also called Cytoxan) each given once every 2 weeks (14 days) for 4 treatments. MEDI 4736 will be given once every 2 weeks, one day after the Doxorubicin and Cyclophosphamide infusion. On Day 2 of each Doxorubicine/Cyclophosphamide chemotherapy immediately before the administration of MEDI4736 you will also receive an injection under the skin with pegfilgrastrim (also called Neulasta). Pegfilgrastim is given to increase bone marrow recovery after chemotherapy and is standard of care therapy.

1. Newly diagnosed histologically confirmed stage I-III, ER, PR and HER2 negative invasive breast cancer as defined by ASCO CAP guidelines for whom systemic chemotherapy would be indicated based on physician judgment following standard NCCN practice guidelines.

2. Patients with prior history of stage I-III breast cancer currently without evidence of metastatic disease are eligible if can tolerate further chemotherapy, patients with newly diagnosed synchronous bilateral breast cancers are also eligible if at least one tumor is triple negative (response will be assessed in both breasts if invasive cancer is present in both)

3. Willing and able to provide written informed consent for voluntary participation in the trial.

4. Willing to undergo a baseline tumor core needle biopsy for correlative science studies. This study does not restrict based on PD-L1 expression because relationship between PD-L1 expression and response is not fully understood and there are no standardized and validated clinical tests to assess PD-L1 expression.

5. 18 years of age or older on the day of signing informed consent.

6. Female subjects must either be of non-reproductive potential (i.e. postmenopausal by history: >/= 60 years old and no menses for >/= 1 year without an alternative medical cause OR history of hysterectomy OR bilateral tubal ligation OR history of bilateral oophorectomy) or must have a negative urine or serum pregnancy test upon study entry.



Hemoglobin ≥ 9.0 g/dl (transfusions allowed)

ANC ≥ 1,500/mm3

Platelets ≥ 100,000/mm3

Total Bilirubin < 1.5 x ULN

AST (SGOT) < 1.5 X ULN

ALT (SGPT) < 1.5 X ULN

INR/PTT < 1.5 x ULN (unless on therapeutic coagulants)

Serum Creatinine


TSH


< 1.5 x ULN


WNL


1. Patients who underwent partial excisional biopsy or lumpectomy, segmental mastectomy or modified radical mastectomy or sentinel node biopsy are not eligible because they cannot be assessed accurately for pathologic response.

2. Patients for whom anthracycline therapy, paclitaxel or antibody therapies are contraindicated :

- Hypersensitivity reactions to any of the medications or to humanized monoclonal antibodies

- History of CHF

- Myocardial infarction within the past 12 months

- Pre-existing peripheral neuropathy ≥ grade 2

- Prior antracycline therapy with ≥ cumulative dose of 240 mg/m2

3. Patients with active autoimmune disease or documented autoimmune disease with 2 years, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, vascular thrombosis associated with antiphosapholipid syndrome, Wegner’s granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis.

4. Patients with hypothyroidism that is clinically stable and have normal TSH levels with hormone replacement, or patients with vitiligo or psoriasis not requiring treatment remain eligible for the study.

5. Active or prior documented inflammatory bowel disease (Crohn’s disease, ulcerative colitis)

6. Patients with known active hepatitis B or C or HIV infection or with history of tuberculosis.

7. Patients with a syndrome that requires administration of chronic systemic steroids or immunosuppressive agents. However, patients that require intermittent use of bronchodilators or local steroid injections are eligible.

8. Attenuated vaccines within 30 days prior to the first doe of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to , the following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, rabies, BCG, and typhoid vaccine.

9. Female patients who are pregnant, breast feeding or male or female patients of reproductive potential who are not employing effective method of birth control.

10. Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736

11. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Bazett’s Corrections.

12. Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/ day of prednicsone or an equivalent corticosteroid.

13. History of primary immunodeficiency

14. History of allogeneic organ transplant

15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric illness/ social situations that would limit compliance with study requirements or compromise the ability of the subject to give informed consent.

16. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.




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HIC:1409014537

Adjuvant

B55: A randomised, double-blind, parallel group, placebo-controlled multi-centre Phase III study to assess the efficacy and safety of olaparib versus placebo as adjuvant treatment in patients with germline BRCA1/2 mutations and high risk HER2 negative primary breast cancer who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy
Contact Treatment Inclusion Criteria Exclusion Criteria Informed Consent


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

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

1. For patients who underwent initial surgery and received adjuvant chemotherapy:

a.) TNBC patients must have been axillary node positive (>=pN1, any tumor size) or axillary node negative (pN0) with invasive primary tumor psize >2cm (>=pT2)

b.) ER and/or PgR +/HER2- patients must have had >=4 pathologically confirmed positive lymph nodes

2. For patients who underwent neoadjuvant chemotherapy followed by surgery:

a.) TNBC patients must have residual invasive breast cancer in the breast and/or resected lymph nodes (non-pCR)

b.) ER and/or PgR +/ HER2- patients must have residual invasive cancer in the breast and/or the resected lymph nodes (non-pCR) AND a CPS&EG score >=3.

3. Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast that is one of the two following phenotypes:

a.) ER and PgR negative AND HER2 negative

b.) ER and/or PgR positive, HER2 negative AND HER2 negative

4. Documented germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious

5. a.) Complete adequate breast surgery

b.) Complete adequate axilla surgery (for Neoadjuvant patients: sentinel lymph node biopsy performed before neoadjuvant chemotherapy- if negative or if lymph nodes only contain micrometastases, additional axillary surgery is not required.

If positive, axillary node dissection or axillary nodal radiotherapy should follow completion of neoadjuvant chemotherapy.)

Sentinel lymph node biopsy performed after neoadjuvant chemotherapy: if negative, addional axilla surgery not mandated.

If positive, additional axillary surgery is required unless the patient is enrolled in Executive Committee approved, Phase III multicenter clinical trial proposing radiotherapy as alternative treatment of axilla.

Axillary dissection.

6. Completed at least 6 cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes, or the combination of both

7. Must have adequate organ and bone marrow function measured within 28 days prior to randomization with no blood transfusions in the past 28 days (Hemoglobin >=10.0 g/dL, ANC >=1.5x10^9/L, platelet count >=100x10^9/L, total biliruin <= ULN, AST (SGOT)/ ALT (SGPT) <=2.5 x ULN, ALP <=2.5xULN

8. Serum creatinine <=1.5xULN

9. ECOG 0-1

10. Postmenopausal or evidence of non-childbearing status

11. FFPE tumor sample from the primary tumor

12. Patient should be randomized in the trial ideally within a maximum of 8 weeks of completion of their last treatment, but in no case longer than 12 weeks



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 wiht 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 realted 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 adminstered 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

HIC:1501015160

A randomized phase III trial of adjuvant therapy comparing doxorubicin plus cyclophosphamide followed by weekly paclitaxel with or without carboplatin for node-positive or high-risk node-negative triple-negative invasive breast cancer
Contact Treatment Inclusion Criteria Exclusion Criteria Informed Consent


Diana Irizarry

Phone:

203-752-6419

Email: diana.irizarry@yale.edu

Active Comparatory: Arm 1 (AC --> WP)

Patients receive doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1.

Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients then receive paclitaxel IV over 60 minutes on day 1.

Treatment repeats weekly for 12 courses in the absence of disease progression or unacceptable toxicity.

Experimental: Arm II

(AC ---> WP + carboplatin)

Patients receive doxorubicin hydrochloride and cyclophosphamide as in Arm I.

Patients then receive paclitaxel IV over 60 minutes on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1.

Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity



1. ECOG Status of 0 or 1

2. Tumor must unilateral invasiv adenocarcinoma of the breast

3. The following staging criterai must be met:

a.) primary tumor must be pT1-3

b.) psilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN2b, pN3a, or pN3b.

c.) If pN0, tumor must be > 3.0 cm

4. Tumor must be HER2-negative, ER-and PgR-negative (<1% ER and PgR considered negative)

5. Patient must have undergone mastectomy or lumpectomy (if lumpectomy, margins must be free of invasive tumor/DCIS; if mastectomy, margins must be free of residual gross tumor.)

6. Patient must have completed one of the following procedures for evaluation of pathologic nodal status:

a.) Sentinel lymphadenectomy,

b.) sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if sentinel node is positive,

c.) axillary lymphadenectomy with or without SN isolation procedure

7. Interval between last surgery for breast cancer and randomization must be no more than 60 days.

8. ANC >= 1200/mm3, platelet count >= 100,000/mm3, and hemoglobin >= 10 g/dL.

9. Total bilirubin <=ULN unless patient has bilirubin elevation > ULN to 1.5 x ULN due to Gilbert's disease/similar syndrome involving slow conjugation of bilirubin; alkaline phosphatase must be <= 2.5 x ULN; AST must be < 1.5 x ULN

10. Patients with AST or alkaline phosphatase > ULN are eligible for inclusion if life imaging performed within 90 days prior to randomization does not demonstrate metastatic disease

11. Patients with alkaline phosphatase > ULN but <= 2.5 x ULN or unexplained bone pain are eligible for inclusion if bone scan, PET-CT scan, or PET scan performed within 90 days prior to randomization does not demonstrate metastatic disease

12. Within 6 weeks prior to randomization, most recent serum creatinine <= ULN or measured or calculated creatinine clearance > 60mL/min

13. LVEF assessment must be performed within 90 days prior to randomization. LVEF must be >=50% regardless of cardiac imaging facility's lower limit of normal



1. T4 tumors including inflammatory breast cancer

2. Clinical or radiologic evidence of metastatic disease

3. Synchronous or previous contralateral invasive breast cancer

4. Previous history of ipsilateral invasiv breast cancer or ipsilateral DCIS

5. History of non-breast malignancies within 5 years prior to randomization

6. Previous therapy with antrhacyclines or taxanes for any malignancy

7. Chemotherapy administered for the currently diagnosed breast cancer prior to randomization

8. Any continued use of sex hormonal therapy (i.e. birth control pills, ovarian hormone replacement)- patients are eligible if these medications are discontinued prior to randomization

9. History of and/or active cardiac disease that would preclude the use of drugs included in treatment

10. Systolic blood pressure > 150 mmHg or diastolic BP > 90 mmHg

11. Active hepatitis B or hepatitis C with abnormal liver function tests

12. HIV positive with a baseline cluster of differentiation (CD)4 count of < 250 cells/mm3 or have history of AIDS indicator conditions

13. Intrinsic lung disease resulting in dyspnea

14. History of hospitalization in past 12 months for diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic nonketotic syndrome (HHNS)

15. Active infection or chronic infection requiring chronic suppressive antibiotics

16. Nervous system disorder >= grade 2

17. Conditions that would prohibit administration of corticosteroids

18. Chronic daily treatment with corticosteroids with a dose of >=10 mg/day methylprednisolone equivalent

19. Known hypersensitivity to any of study drugs or excipients

20. Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up

21. Psychiatric or addictive disorders that would preclude the patient from meeting the study requirements

22. Pregnancy and lactation at time of study entry

23. Use of any investigational product within 4 weeks prior to randomization


Main CAF


CAF - ST Francis

HIC1509016533

Randomized Phase III Trial Evaluating the Role of Weight Loss in Adjuvant Treatment of Overweight and Obese Women with Early Breast Cancer
Contact Treatment Inclusion Criteria Exclusion Criteria Informed Consent

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


HIC: 1607018037

A Randomized Phase III Post-Operative Trial of Platinum Based Chemotherapy Vs. Capecitabine in Patients with Residual Triple-Negative Basal-Like Breast Cancer following Neoadjuvant Chemotherapy
Contact Treatment Inclusion Criteria Exclusion Criteria Informed Consent


Courtney Frederick,

Tel: 203-737-7992;

Fax: 203-785-4069

email:courtney.frederick@yale.edu

This study has three study groups.

• Group 1 will receive observation. However, this group is no longer adding patients.

• Group 2 will get a platinum-based chemotherapy treatment for 12 weeks. You and your doctor will get to choose between cisplatin or carboplatin.

• Group 3 will get the usual approach used for this type of cancer: capecitabine for 18 weeks.


If you get randomized to the platinum-based chemotherapy group (Group 2), you will receive a 30-minute intravenous infusion (IV through the vein) of either cisplatin or carboplatin once, every 3 weeks, for 4 doses (total of 12 weeks). After you finish the platinum-based chemotherapy, your doctor will continue to watch you for side effects and follow your condition for about 10 years (every 3 months if you are less than 2 years from study entry, every 6 months if you are 2-5 years from study entry, every 12 months if you are 5-10 years from study entry).

If you get randomized to the usual approach group (Group 3), you will receive capecitabine pills for a total of 6 cycles (total of 18 weeks). Each cycle is 3 weeks long. In these cycles you will take the pills twice a day for 2 weeks and then get one week off. Capecitabine pills should be taken within 30 minutes after a meal. You will be required to complete a medication diary and bring it to each medication visit along with any unused pills in the pill bottle. After you finish the capecitabine chemotherapy, your doctor will continue to watch you for side effects and follow your condition for about 10 years (every 3 months if you are less than 2 years from study entry, every 6 months if you are 2-5 years from study entry, every 12 months if you are 5-10 years from study entry).



STEP 0

********************************

1. Age ≥ 18 years

2. ECOG Performance Status 0 or 1 within 2 weeks prior to screening

3. Female and male patients must have histologically confirmed triple negative (ER-/PR-/HER2-) invasive breast cancer, clinical stage II-III at diagnosis (AJCC 7th edition) based on initial evaluation by clinical examination and/or breast imaging.

ER- and PR- should meet one of the following criteria:

____ ≤ 10% cells stain positive, with weak intensity score (Allred score ≤ 3)

____ ≤ 1% cells stain positive, with weak or intermediate intensity score (Allred score ≤ 3)


HER2 negative (not eligible for anti-HER2 therapy) will be defined as:

____ IHC 0, 1+ without ISH HER2/neu chromosome 17 ratio OR

____ IHC 2+ and ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than

2.0 and if reported average HER2 copy number < 6 signals/cells OR

____ ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if

reported average HER2 copy number < 6 signals/cells without IHC)


NOTE: Patients that originally present with synchronous bilateral tumors are eligible provided both tumors are TNBC, and at least one of them fulfills the remainder eligibility criteria of the protocol.

4. Patients must have completed neoadjuvant taxane +/- anthracycline. Patients must NOT have received cisplatin or carboplatin or capecitabine as part of their neoadjuvant therapy regimen.

NOTE: Patients who received preoperative therapy as part of a clinical trial may enroll.

5. Must have completed definitive resection of primary tumor.

• Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however patients with positive margins may enroll if the treatment team believes no further surgery is possible and patient has received radiotherapy. Patients with margins positive for lobular carcinoma in situ (LCIS) are eligible.

• Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable.

• Sentinel node biopsy post neoadjuvant chemotherapy (i.e. at the time of definitive surgery) is allowed. Axillary dissection is encouraged in patients with lymph node involvement, but is not mandatory.

6. Post neoadjuvant chemotherapy, patients must be found to have residual invasive cancer in the breast at the time of definitive surgery. Residual cancer is defined as a contiguous focus of residual invasive cancer, in the breast, measuring ≥ 1 cm in diameter, and with more than minimal cellularity, as per local pathologist determination.

NOTE: The presence of ductal carcinoma in situ (DCIS) without

invasion does not qualify as residual invasive disease in the breast.

7. Post-mastectomy radiotherapy is required for all patients with the following:

____ Primary tumor ≥ 5 cm (prior to neoadjuvant chemotherapy [clinically] or at the time of definitive surgery) or involvement of 4 or more lymph nodes at the time of definitive surgery.

____ For patients with primary tumors < 5 cm or with < 4 involved lymph nodes prior to neoadjuvant chemotherapy and at the time of definitive surgery, provision of post mastectomy radiotherapy is at the discretion of the treating physician.

NOTE: Radiation of regional nodal basins is at the discretion of the treating radiation oncologist. Patients enrolled in clinical trials addressing local therapy after neoadjuvant chemotherapy are allowed to enroll.

8. Adequate bone marrow and organ function based on the following tests. Laboratory values must be obtained within 8 weeks prior to screening for protocol therapy:

Value Date of Test

Hemoglobin ≥ 9.0 g/dl ___________ ___________

Platelets ≥ 100,000/mL ___________ ___________

Absolute neutrophil count (ANC)


Calculated Creatinine Clearance

> 1500 cells/mm3



> 50 mL/min using the Cockcroft-Gault formula:

Males:

(140 – Age in years) × Actual Body Weight in kg

72 × Serum Creatinine (mg/dL)

Females: Estimated creatinine clearance for females × 0.85

Total Bilirubin ≤ 1.5 ULN (or ≤ 3.0 mg/dL for Gilbert’s Disease) ___________ ___________

AST (SGOT) ≤ 2.5 X ULN ___________ ___________

ALT (SGPT) ≤ 2.5 X ULN __________ ___________

9. No stage IV (metastatic) disease, however no specific staging studies are required in the absence of symptoms or physical exam findings that would suggest distant disease.

10. No clinically significant infections as judged by the treating investigator.

11. Patients with active ≥ CTCAE v.4 grade 2 neuropathy are ineligible.

12. Adjuvant chemotherapy after surgery other than that specified in this

protocol is not allowed. LHRH agonists and adjuvant bisphosphonate or denosumab use is allowed.

13. Patients must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the residual disease on the definitive surgical specimen available for PAM50 analysis for stratification.

• Tumor tissue specimen from the definitive surgery has been collected and is ready to ship to the ECOG-ACRIN Central Biorepository and Pathology Facility (CBPF) within

21 weeks post-surgery as indicated in Section 10.2.1.

The Molecular Diagnostics Laboratory (MDL) at MD Anderson Cancer Center will

perform the PAM50 analysis and notify the ECOG-ACRIN Operations Office within

three (3) weeks of receipt of the tumor tissue specimen via secure electronic

messaging to the ECOG-ACRIN database.

NOTE: Every effort should be made to submit the tumor tissue specimen to the ECOG-ACRIN CBPF immediately.


STEP 1

********************************

1. Must have PAM50 analysis by digital mRNA quantitation on the formalin-fixed paraffin-embedded tumor tissue specimen (FFPE) of the residual disease in the breast or axilla resected at the time of definitive surgery completed. Date notified of eligibility per central PAM50 analysis:_________

2. ECOG Performance Status 0 or 1 within 2 weeks prior to randomization

3. Patients must have completed adjuvant radiotherapy ≥ 2 weeks prior to randomization for protocol therapy, if applicable.

4. Patients must have completed treatment with any investigational agent ≥ 30 days prior to randomization for protocol therapy, if applicable.

5. Patients must be randomized within 24 weeks from surgery

6. Women must not be pregnant or breast-feeding due to risk of teratogenicity/ toxicity with capecitabine or platinum based therapy. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy.

A female of childbearing potential is any woman, regardless of sexual orientation or

whether they have undergone tubal ligation, who meets the following criteria:

1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been

naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Date of pregnancy blood test or urine study: ___________



7. Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study.

8. Adequate bone marrow and organ function based on the following tests. Laboratory values must be obtained within 2 weeks prior to randomization.



Value Date of Test

> 9.0 g/dl ___________ ___________

> 100,000/mL ___________ ___________

> 1500 cells/mm3



≤ 2 for subjects not on anticoagulants; INR ≤ 3 for subjects on warfarin



> 50 mL/min using the Cockcroft-Gault formula:

Males:

(140 – Age in years) × Actual Body Weight in kg

72 × Serum Creatinine (mg/dL)

Females:

Estimated creatinine clearance for females × 0.85

≤ 1.5 ULN (or ≤ 3.0 mg/dL for Gilbert’s Disease) ___________ ___________

≤ 2.5 X ULN ___________ ___________

≤ 2.5 X ULN __________ ___________






NA


Main CAF



HIC1607018160

A Randomized, Phase III Trial to Evaluate the Efficacy and Safety of MK-3475 as Adjuvant Therapy for Triple Receptor-Negative Breast Cancer with > 1 cm Residual Invasive Cancer or Positive Lymph Nodes (>pN1mic) After Neoadjuvant Chemotherapy
Contact Treatment Inclusion Criteria Exclusion Criteria Informed Consent


Courtney Frederick,

Tel: 203-737-7992;

Fax: 203-785-4069

email:courtney.frederick@yale.edu

MK-3475 or Placebo in the adjuvant setting for TNBC.


Step 1

1. Patients must have histologically confirmed ER-, PR- and HER2-negative (triplenegative, TNBC) with residual invasive breast cancer, as defined by the 2010 and 2013 ASCO CAP guidelines, after completion of neoadjuvant chemotherapy. Residual disease must be ≥ 1 cm in greatest dimension, and/or have positive lymph nodes (ypN+) observed on pathologic exam.


NOTE: IHC-positive isolated tumor cells in the lymph node (N0 [i+]) are not considered node-positive and these patients also must have ≥ 1 cm residual invasive cancer in the breast in order to be eligible.

2. Patients must not have metastatic disease (i.e., must be M0).

3. It is preferred that axillary lymph node sampling is performed after completion of neoadjuvant chemotherapy to allow more accurate assessment of pathologic response. Patients must have a complete axillary lymph node dissection after neoadjuvant chemotherapy in the following situations (exceptions will be granted for patients participating in the Alliance A11202 trial):

• Patients had documented pathologic involvement of the axillary nodes (FNA or core biopsy) before neoadjuvant chemotherapy and had sentinel node biopsy after neoadjuvant chemotherapy with positive sentinel node(s).

• Patient had documented pathologic involvement of the axillary nodes (FNA or core biopsy) before neoadjuvant chemotherapy and had only 1 sentinel lymph node removed after neoadjuvant chemotherapy.

NOTE: Patients who undergo sentinel node biopsy before starting neoadjuvant treatment and do not undergo post neoadjuvant assessment of the axillary nodes or who have negative axillary nodes on post neoadjuvant assessment must have ≥ 1 cm residual invasive cancer in the breast after completion of neoadjuvant chemotherapy


4. Patients must have a minimum of five, available unstained slides from the residual (post-neoadjuvant) invasive tumor in primary site or lymph node to be submitted within 7 days after registration to determine PD-L1 expression as described in Section 15.1. The tumor tissue must be adequate for PD-L1 testing, which typically requires a minimum of 100 cancer cells per slide.

5. Patients must be offered the opportunity to participate in specimen banking as outlined in Section 15.4.

6. Patients must have had neoadjuvant chemotherapy followed by surgery. The recommended neoadjuvant treatment should include 16-24 weeks of a third generation chemotherapy regimen as recommended by NCCN guidelines for triple negative breast cancer (examples include dose dense AC followed by dose-dense paclitaxel; weekly paclitaxel x 12 followed or preceded by FAC, FEC, AC or dose dense AC; docetaxel either followed or preceded by FEC/FAC or AC. Carboplatin containing neoadjuvant chemotherapy is also allowed). Patients who cannot complete all planned treatment cycles for any reason are considered high risk and therefore are eligible for the study if they have residual disease. Patients must have resolution of adverse event(s) of the most recent prior chemotherapy to Grade 1 or less, except alopecia and ≤ Grade 2 neuropathy which are allowed.

7. Patients may receive post-operative (adjuvant) chemotherapy for up to 24 weeks of duration (e.g. 8 cycles of capecitabine as in the CREATE-X trial) after completion of surgery at the discretion of the treating physician. Patients must have resolution of adverse event(s) of the most recent prior chemotherapy to Grade 1 or less, except alopecia and ≤ Grade 2 neuropathy which are allowed. Adjuvant chemotherapy, if administered, must have been completed within 35 days prior to screening registration and must be given prior to radiation.

Inclusion Criteria

(must all be answered Yes)

8. Patients must have completed their final breast surgery (rendering them free from disease) with clear resection margins for invasive cancer and DCIS within 90 days prior to screening registration for patients not receiving post-operative (adjuvant) chemotherapy, or within 210 days prior to screening registration for patients who have completed post-operative (adjuvant) chemotherapy. Positive margins are allowed only if the surgical team of the patient deems further resection impossible.


9. Patients for whom radiation therapy (RT) to the affected breast or chest wall and regional nodal areas is clinically indicated as per NCCN treatment guidelines, should receive RT after randomization when possible, concomitant with MK-3475 (pembrolizumab) if randomized to the experimental arm. However, RT administered prior to registration is also allowed. Patients must specify at the time of screening registration whether or not they will receive RT and the extent of intended RT.

10. Patients must not have had prior immunotherapy with anti-PD-L1, anti-PD-1, antiCTLA4 or similar drugs. Patients must not be planning to receive any of the prohibited therapies listed in Section 7.3 during the screening or treatment phases of the study.

11. Patients must not be planning to receive concomitantly other biologic therapy, hormonal therapy, other chemotherapy, surgery or other anti-cancer therapy except radiation therapy while receiving treatment on this protocol.

12. Patients must be women or men ≥ 18 years of age.

13. Patients must have Zubrod Performance Status ≤ 2.

14. Patients must not have a history of (non-infectious) pneumonitis that required steroids or evidence of active pneumonitis.

15. Patients must not have an active infection requiring systemic therapy.

16. Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

17. Patients must not have received live vaccines within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

18. Patients must not have known active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection prior to registration. Patients who have completed curative therapy for HCV are eligible. Patients with known HIV infection are eligible if they meet each of the following 3 criteria:

• CD4 counts ≥ 350 mm3

• Serum HIV viral load of < 25,000 IU/ml and

• Treated on a stable antiretroviral regimen

19. No other prior invasive malignancy is allowed except for the following: adequately treated basal (or squamous cell) skin cancer, in situ breast or cervical cancer. Stage I or II invasive cancer treated with a curative intent without evidence of disease recurrence for at least five years.

20. Patients must be informed of the investigational nature of this study and must sign and give written informed consent for this protocol in accordance with institutional and federal guidelines.

21. Patients must be informed of the investigational nature of this study and must sign and give written informed consent for this protocol in accordance with institutional and federal guidelines.


Step 2

1. Patients must not be registered to Step 2 until receiving confirmation from the SWOG Statistical Center that the patient's tissue specimen was adequate for PD-L1 testing. Patients must be registered within 7 days of receiving the e-mail notification confirming submission was evaluable for PD-L1 status.

2. A serum TSH must be obtained within 28 days prior to Step 2 registration to obtain a baseline value. Date : ___________


Patients must have adequate bone marrow, hepatic and renal function within 28 days defined as:


Value Date of Test

Hemoglobin ≥ 9.0 g/dl ___________ ___________

ANC ≥ 1,500/mm3 ___________ ___________

Platelets ≥ 100,000/mm3 ___________ ___________

Total Bilirubin ≤ 1.5 x ULN (except Gilberts, must have bili < 3.0 g/dl) ___________ ___________

AST (SGOT) ≤ 2.5 X ULN ___________ ___________

ALT (SGPT) ≤ 2.5 X ULN ___________ ___________

Serum Creatinine



≤ IULN or calculated creatinine clearance ≥ 60 ml/min















NA




HIC 2000020555

Metastatic

A PHASE I, OPEN LABEL, DOSE-ESCALATION STUDY TO EVALUATE THE SAFETY AND TOLERABILITY OF SGN-LIV1A IN PATIENTS WITH LIV-1-POSITIVE METASTAIC BREAST CANCER
Contact Treatment Inclusion Criteria Exclusion Criteria Informed Consent

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


A phase I/II clinical trial evaluating the safety and clinical activity of radioiodide (131I-) as a novel targeted therapy for metastatic breast cancer that overexpresses functional Na/I symporter
Contact Treatment Inclusion Criteria Exclusion Criteria Informed Consent

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

HIC:1607018035

A PHASE II STUDY WITH ORTERONEL AS MONOTHERAPY IN PATIENTS WITH METASTATIC BREAST CANCER (MBC) THAT EXPRESSES THE ANDROGEN RECEPTOR (AR)
Contact Treatment Inclusion Criteria Exclusion Criteria Informed Consent

Courtney Frederick

Office Phone: 203-737-7992

Fax: 203-785-5792

e-mail: courtney.frederick@yale.edu

Orteronel 300mg po BID (total daily dose of 600mg).

1.Androgen Reveptor positive (AR+) breast cancer defined as ≥10% staining by immunohisto-chemistry. Tumor tissue from a primary biopsy or metastatic lesion is mandatory. Submision of tissue for AR assessment confirmation at the central laboratory.

2.In addition to having AR+ tumors, patients must fit into 1 of the 2 following categories:

◦Triple Negative Breast Cancer : Must have received at least 1 and up to 3 prior chemotherapy regimens for metastatic disease.

◦HER2+ patients in this group must have received a minimum of 2 lines of HER2-directed therapy for metastatic cancer.

3.Patients with bone only metastasis are eligible.

4.Both female and male patients are eligible.

5. Lab:

  • ANC ≥ 1.25 x 109/L
  • Platelet count ≥ 75 x 109/L
  • Hemoglobin ≥ 9.0 g/dL
  • Serum creatinine ≤1.5 x ULN or creatinine clearance ≥40 mL/min as calculated by the Cockcroft-Gault method
  • Serum AST and ALT ≤ 2.5 x the upper limit of normal (ULN), if no liver involvement
  • Serum total bilirubin (TBILI) ≤ 1.5 ×ULN patients with known Gilbert Syndrome, a total bilirubin ≤3.0 x ULN, with direct bilirubin ≤1.5 x ULN)
  • AST and ALT ≤5 ULN in case of liver metastases

6.Screening calculated LVEF of ≥50% by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan

7. Life expectancy of ≥3 months

1.Known hypersensitivity to orteronel or to orteronel excipients

2.Patients receiving other anticaner treatment for breast cancer (Receiving chronic bisphosphonate or denosumab therapy are eligible).

3.Prior anti-androgen therapy

4.Use of an investigational drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of orteronel, or concurrent treatment. For investigational drugs for which 5 half-lives is less than 21 days, a minimum of 10 days between termination of the investigational drug and administration of orteronel is required.

5.Active brain metastases or leptomeningeal disease. Previously treatedbrain metastases that are stable for at least 3 months are allowed. Patients must be off steroids, but anti-convulsants are allowed.

6.Adrenal insufficiency, or patients receiving treatment with ketoconazole, abiraterone, or aminoglutethimide.

7.Wide field RT (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field RT for palliation ≤7 days prior to study drug

8.Major surgical procedures ≤28 days of beginning study treatment or minor surgical procedures ≤7 days.

9.Active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy.

10.Active/serious cardiac disease, thromboembolic events, or any other cardiac condition within 6 months prior to study drug. Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed.

11.ECG abnormalities of Q-wave infarction, unless identified 6 or more months prior to screening or QTc Fridericia (F) interval >460 msec

12.Inadequately controlled hypertension

13.HIV, active chronic HBV, or HCV, life-threatening illness unrelated to cancer, or any serious medical or psychiatric illness.

14.Uncontrolled DM (Type II DM are eligible if they require only oral hypoglycemic agents and fasting blood glucose level is ≤120. Type I DM are eligible if HbAlc is ≤7).

CAF - main



Pre-screen

HIC:1404013697

A Phase II Clinical Trial of Pembrolizumab (MK-3475) as Monotherapy for Metastatic Triple-Negative Breast Cancer (mTNBC)
Contact Treatment Inclusion Criteria Exclusion Criteria Informed Consent

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


Cohort A: Pembrolizumab as 2L+ monotherapy for mTNBC


Cohort B: Pembrolizumab as 1L monotherapy for PD-L1 (+) mTNBC


Cohort C: Expansion of the PD-L1 strong (+) subpopulation from Cohort A


For Cohorts A and C (2L+ monotherapy):

1. Have received at least one systemic treatment for metastatic breast cancer and have documented disease progression on the most recent therapy. Subjects must have been previously treated with an anthracycline and a taxane in the (neo)adjuvant or metastatic setting


For Cohort B (1L monotherapy):

2. Have not yet received prior systemic anti-cancer therapy for mTNBC and

3 . Have PD-L1 (+) mTNBC


For Cohort C (2L+ monotherapy):

4. Have PD-L1 strong (+) mTNBC (i.e. subject's tumor must meet or exceed the PD-L1 cut point for high positivity) or all cohorts, potential subjects must:

5. Have provided tumor tissue for PD-L1 biomarker analysis from a newly obtained core or excisional biopsy of a metastatic tumor lesion not previuosly irradiated (mandatory).

a. Note: subjects for whom tumor biopsies cannot be freshly obtained may submit an archived metastatic tumor specimen only upon agreement from the Sponsor

6. Have measurable metastatic disease based on RECIST 1.1 as determined by the central imaging vendor.

7. Have a performance status of 0 or 1 on the ECOG performance scale. Assessment should be performed within 10 days of treatment initiation.

8. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity. Male subjects should agree to use an adequate method of contraception.

9. Demonstrate adequate organ function.



1. Subject is currently participating and receiving study stherapy, or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.

2. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment.

3. Has a diagnosis of immunodeficieny or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

4. Has had a prior anti-cancer monoclonal antibody for direct anti-neoplastic treatment within 4 weeks prior to study Day 1 or what hoas not recovered from adverse events due to agents administered more than 4 weeks earlier

5. Has had prior chemotherapy, targeted small molecular therapy, or radiation therapy within at least 2 weeks prior to study Day 1 or who had not recovered from adverse events due to a previously administered agent.

6. Has a known additional malignancy that progressed or required active treatment within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamos cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.

7. Has radiographically detectable central nervous system metastases and/or carcinomatous meningitis.

8. Has history of pneumonitis requiring treatment with steroids or history of interstitial lung disease

9. Has an active infection requiring systemic therapy.

10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in teh best interest of the subject to participate, in the opinion of the treating investigator

11. Has known psychiatric or substance abuse disorders that would intefere with cooperation with the requirements of the trial.

12. Is pregnant or breastfeeding, or expecting to conceive or father children within the proejcted duration of the trial.

13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor or has participated in Merck MK-3475 trials.

14. Has a known history of HIV

15. Has known active Hepatitis B or Hepatitis C

16. Has received a live vaccine within 30 days of planned start of study therapy




consent



HIC1506016051

A Phase II Multiple-Arm, Open-Label, Randomized Study of PARP inhibition (ABT-888; veliparib) and Anti-PD-L1 Therapy (Atezolizumab; MPDL3280A) Either alone or in Combination in Homologous DNA Repair (HDR) Deficient Triple Negative Breast Cancer (TNBC)
Contact Treatment Inclusion Criteria Exclusion Criteria Informed Consent


Clinical Research Coordinator

Caroline Hotchkiss, MPH, CCRP

Office: (203) 737-5228 Cell: (203) 903-3405

Email: caroline.hotchkiss@yale.edu

Clinical Research Assistant

Stephanie Vetter

Work Phone: (203) 785.2963

Fax: (203) 785.4069

Patient population: BRCA1/2 mutated TNBC

Randomized 1:1:1

ABT-888 400 mg PO bid continuously

atezolizumab 1200 mg IV every 3 weeks

ABT-888 400 mg PO bid continuously in combination with atezolizumab 1200 IV every 3 weeks

3 biopsies:

baseline

time of first tumor assessment scan (6 weeks from the start of treatment)

disease progression


Patients on monotherapy arms: cross-over to combination arm allowed following disease progression

Initial safety review will occur in the first 6 patients randomized to combination ABT-888+atezolizumab

If unacceptable toxicity occurs in 2 of these initial 6 patients, dose de-escalation will occur




  1. Histologically documented unresectable stage III or IV TNBC and a known BRCA 1/2 mutation present
    1. Her-2 negative, ER negative (< 1% ER by IHC) and PR negative (< 1% PR staining by IHC)
  2. Measurable disease, accessible for biopsy
  3. Age ≥18 years
  4. ECOG performance status ≤2
  5. Life expectancy > than 6 months
  6. Ability to swallow and retain oral medication
  7. Select allowed prior therapies:
    1. ≤ 3 lines of prior therapy in metastatic setting
    2. Prior chemotherapy allowed, including platinum therapy (> 4 weeks from last dose)
    3. Prior radiation therapy

i. minimal (≤5% of their total marrow volume) within 3 weeks

ii. >5% of total marrow volume within 4 weeks

iii. > 50% of total marrow volume excluded

    1. Anti-CTLA-4 therapies (>6 weeks from last dose)
    2. Systemic immunosuppressive medication (>2 weeks from last dose)
  1. Normal organ function as defined:
    1. absolute neutrophil count ≥1,500/mcL
    2. platelets ≥100,000/mcL
    3. Hemoglobin ≥ 8 g/dL
    4. total bilirubin ≤ 1.5 x ULN
    5. AST(SGOT)/ALT(SGPT) ≤ 3 × ULN if no liver metastasis; ≤ 5 x upper ULN if liver metastasis present
    6. alkaline phosphatase ≤2.5 × ULN (<=5 x ULN for patients with documented liver involvement or bone metastases)
    7. creatinine clearance ≥30 mL/min/1.73 m2 by Cockcroft-Gault
    8. INR and aPTT <=5 x ULN



1. Prior allogeneic bone marrow transplantation or prior solid organ transplantation

2. Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases (asymptomatic treated or untreated CNS disease may be enrolled, given specific condisions specified in protocol)

3. Prior treatment with any PARP inhibitor or any anti-PD-1/anti-PD-L1 antibody

4. History of severe allergic, anaphylactic, or other hypersensitivity reactions to:

5. chimeric or humanized antibodies or fusion proteins

6. Chinese hamster ovary cell products

7. compounds of similar chemical or biologic composition to ABT-888 and/or atezolizumab

8. Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease

9. History or risk of autoimmune disease

10. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia or evidence of active pneumonitis on screening chest computed tomography (CT) scan

11. Major surgical procedure within 28 days

12. Administration of a live, attenuated vaccine within 4 weeks

13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

14. Pregnant women

15. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1

16. Patients with active seizures or a history of uncontrolled seizure disorder, including focal or generalized seizure within the past year



HIC 1608018258