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NCT# NCT02538471 WCM IRB # 1505016222 Title: LY2157299

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NCT# NCT02538471 WCM IRB # 1505016222 Title: LY2157299 NCT# NCT02538471 WCM IRB # 1505016222 Title: LY2157299 Monohydrate (LY2157299) and Radiotherapy in Metastatic Breast Cancer Final Approved version date: 04.21.2017 IRB approval date: May 19th, 2017. Document History Amendments Version Version Date Protocol Amendment 4 4.0 04.21.2017 Protocol Amendment 3 3.0 11.22.2016 Protocol Amendment 2 2.1 07.18.2016 Protocol Amendment 1 2.0 09.29.2015 Initial Protocol 1.0 07.10.2015 Protocol # 1505016222 IND # 126952 Version Date 04/21/2017 Co-Investigators UCLA: 2 Protocol # 1505016222 IND # 126952 Version Date 04/21/2017 Study Contact at WCM: Sharanya Chandrasekhar 3 Protocol # 1505016222 IND # 126952 Version Date 04/21/2017 Participating Sites: 1. New York-Presbyterian Weill Cornell Medicine Stich Radiation N-046 525 East 68th street, New York, NY – 10065 2. David Geffen School of Medicine at UCLA 10833 Le Conte Avenue Los Angeles, CA 90095-1714 4 Protocol # 1505016222 IND # 126952 Version Date 04/21/2017 Confidentiality Statement This document is confidential and is to be distributed for review only to investigators, potential investigators, consultants, study staff, and applicable independent ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without written authorization from WCM. 5 Protocol # 1505016222 IND # 126952 Version Date 04/21/2017 List of Abbreviations All abbreviations used throughout the protocol must be defined. 1D11 Murine monoclonal antibody against TGFΒ 4T1 murine murine breast tumor model model ADL Activities of daily living AE Adverse event AE Adverse Event Akt Agammaglobulinemia Tyrosine Kinase) ATM Ataxia Telangectasia Mutated AUC Area Under the Curve - a measure of total drug concentration in blood plasma over a period of time BCC Basal Cell Carcinomas B-HCG Beta Human Chorionic Gonadotrophin BUN Blood Urea Nitrogen CAT Cambridge Antibody Technology CBC Complete blood count CHF Congestive Heart Failure CI Confidence interval CIN Cervical Intraepithelial Neoplasia Cmax Maximum concentration of drug CNS Central nervous system CR Complete response CRF Case report/Record form CTCAE Common Terminology Criteria for Adverse Events DC Dendritic Cells DDR DNA Damage Response DLT Dose Limiting Toxicity DSMB Data Safety Monitoring Board DTC Disseminated Tumor Cells ECG Electrocardiogram ECM Extra Cellular Matrix EGFR Epidermal Growth Factor Receptor ELISA Enzyme-Linked Immunosorbent Assay 6 Protocol # 1505016222 IND # 126952 Version Date 04/21/2017 EMT Epithelial-Mesenchymal Transdifferentiation ER Estrogen Receptor ERK Extracellular Signal-Regulated Kinase FSGS Focal Segmented Glomerulosclerosis GC1008 Fresolimumab, human IgG4 kappa monoclonal antibody against TGFΒ GI Gastrointestinal Hct Hematocrit Hgb Hemoglobin HIV Human Immunodeficiency Virus HLA-A2 MHC Class I, A cell surface antigen: Human Leukocyte Antigen serotype within HLA-A "A" serotype group HPF High-power field HTN Hypertensions IL-6 Interleukin-6 IPF Idiopathic Pulmonary Fibrosis IRB Institutional Review Board irRC Immune response criteria IV Intravenous JNK c-Jun N-terminal protein Kinase KA Keratoacanthoma Kd Dissociation Constant LAP Latency-Associated Protein LY2157299 LY2157299 Monohydrate MAPK Mitogen-Activated Protein Kinase MDA-MB- human breast cancer cell line 231 MHC-I Major Histocompatibility Complex class I NCI National Cancer Institute NK Natural Killer Lymphocytes nM Nanomolar NOAEL No-Observed-Adverse-Effect Level OS Overall survival PBMC Peripheral Blood Mononuclear Cells PD Pharmacodynamic PFS Progression free survival 7 Protocol # 1505016222 IND # 126952 Version Date 04/21/2017 PI3K Phosphoinositide 3-Kinase PLT Platelet PO Per Os – orally PR Partial response PSA Prostate-Specific Antigen PTHrP Parathyroid Hormone-related Peptide RCC murine renal cell carcinoma (RENCA) RECIST Response evaluation criteria in solid tumors RT Radiation Therapy SAE Serious adverse event SC subcutaneous SCC Squamous Cell Carcinomas SD Stable disease Smad Sma- [small body size] and Mad-related protein sur1M2 synthesized analogue of survivin in which a better anchor residue (methionine) replaces the natural threonine at position 2 so as to better bind HLA-A2 TRII:Fc soluble type II TGFΒ receptor:Fc fusion protein TBRS TGFβ gene Response Signature TGFΒ Transforming Growth Factor-beta TGFΒR Transforming Growth Factor-beta Receptor TNFR Tumor Necrosis Factor Receptor T-reg Regulatory T cells TTP Time to progression ULN Upper limit of normal USP United States Pharmacopoeia CFR Code of Federal Regulations CRF Case Report Form DSMB Data Safety Monitoring Board DSMP Data Safety Monitoring Plan FDA Food and Drug Administration GCP Good Clinical Practice HRBAF Human Research Billing Analysis Form ICF Informed Consent Form IND Investigational New Drug 8 Protocol # 1505016222 IND # 126952 Version Date 04/21/2017 IRB Institutional Review Board PHI Protected Health Information PI Principal Investigator REDC Research Electronic Data Capture SAE Serious Adverse Event SUSAR Suspected Unexpected Serious Adverse Reaction WCM Weill Cornell Medicine UAP Unanticipated Problem HIPAA Health Insurance Portability and Accountability Act of 1996 9 Protocol # 1505016222 IND # 126952 Version Date 04/21/2017 Document History Amendments Version Version Date Protocol Amendment 4 4.0 04.21.2017 Protocol Amendment 3 3.0 11.22.2016 Protocol Amendment 2 2.1 07.18.2016 Protocol Amendment 1 2.0 09.29.2015 Initial Protocol 1.0 07.10.2015 Summary of changes: Protocol Amendment 4 Version 4.0 dated 04.21.2017 1. Removal of the following cardiotoxicity testing; hsCRP, Cystatin C and BNP. Due to a change in WCM processing procedures, hsCRP, cystatin C and BNP testing are no long being processed at WCM and are now being sent to an outside lab which takes 7-10 days to be resulted. Due to the delay in receiving the results we are removing these labs so as to not delay the enrollment of metastatic breast cancer patients onto this study. 2. Per DSMB recommendation, the Data Safety Monitoring Plan section 12.1 has been revised to reflect the study will be reviewed on an annual basis. 3. Pre study and On study evaluations have been amended to include the following: A. Patients must have an MRI of the brain. A Brain CT with contrast is also acceptable B. Patients must also have a PET/CT or a CT of the Chest/Abdomen/ Pelvis C. Patients can begin two weeks from prior treatment if they are asymptomatic from previous therapy Summary of changes: Protocol Amendment 3 version 3.0 dated 11.22.2016 1. DoD requested changes: Research Monitor responsibilities – Section 12. 2. WCM DSMB recommendation for semi-annual review – letter dated 10.20.2016. Summary of changes: Amendment 2 dated 07.18.2016 1. Data safety Monitoring board recommendations from 03.24.2016 were added to the protocol section 12.1. “The WCM DSMB is to perform a data and safety analysis every three months (quarterly) following the accrual of the first subject”. Summary of Changes: Amendment 1 09.29.2015 1. Adding Maria Fenton-Kerimian as the Research Nurse 10 Protocol # 1505016222 IND # 126952 Version Date 04/21/2017 2. Data Safety Monitoring board review modifications 11 Protocol # 1505016222 IND # 126952 Version Date 04/21/2017 PROTOCOL SUMMARY TGFβ blockade will enhance response of irradiated tumors and improve the function of Dendritic and T cells. Full Title: LY2157299 Monohydrate (LY2157299) and Radiotherapy in Metastatic Breast Cancer Short Title: LY2157299 and Radiotherapy in Metastatic Breast Cancer Clinical Phase: Phase II Principal Investigator: Dr. Silvia C. Formenti, M.D. Sample Size: N= 28 (WCM will enroll a total of 18 patients and UCLA will enroll 10 patients) Accrual Ceiling: 35 Study Population: Patients must have biopsy proven metastatic breast cancer and have stable disease or progressed after at least one course of chemotherapy or hormonal therapy. This study will not enroll vulnerable population. Women > 18 years and < 90 years. Accrual Period: 3 years Study Design: TGFΒ blockade will enhance response of irradiated tumors and improve the function of Dendritic and T cells. Patients will receive 300 mg/day of study drug administered via oral drug tablet every day for 14 days on and 14 days off (=28 day cycle). Radiation to a metastatic site will be delivered at a dose of 7.5 Gy, given consecutively on days 1-3-5. Study Duration: Study participation will involve 15 visits over the course of 16 weeks (approx.4 months). Patients will have an annual follow-up up to 5 years. Study Agent/ Intervention Description: LY2157299 will be administered oral drug tablet: 300mg/day. Patients will receive 300 mg/day of study drug administered via oral drug tablet every day for 14 days on and 14 days off (=28 day cycle) . Primary Objective: 1. to assess safety and feasibility of combining TGFβ receptor I kinase inhibitor LY2157299 and local radiotherapy 2. To determine if treatment with TGFΒ receptor I kinase inhibitor LY2157299 and localized RT achieves an abscopal tumor regression; Secondary Objectives: 1. to estimate the local response rate of combining TGFΒ receptor I kinase inhibitor LY2157299 and local radiotherapy 2. To determine if treatment with TGFΒ receptor I kinase inhibitor LY2157299 and localized RT enhances tumor-specific immunity in 12 Protocol # 1505016222 IND # 126952 Version Date 04/21/2017 patients with metastatic breast cancer, and if this is associated with abscopal tumor regression. 3. To determine if treatment with TGFΒ receptor I kinase inhibitor LY2157299 and localized RT alters the numbers and function of T- reg cells in patients with metastatic breast cancer. Endpoints: Primary Endpoint: A. To assess safety and feasibility of combining TGFβ receptor I kinase inhibitor LY2157299 and local radiotherapy B. To determine if treatment with TGFΒ receptor I kinase inhibitor LY2157299 and localized RT achieves an abscopal tumor regression Secondary Endpoint: A. to estimate the local response rate of combining TGFβ receptor I kinase inhibitor LY2157299 and local radiotherapy, B. to determine if treatment with TGFβ receptor I kinase inhibitor LY2157299 and localized RT enhances tumor-specific immunity in patients with metastatic breast cancer, and if this is associated with abscopal tumor regression.
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