LY2157299 Monohydrate (LY2157299) and Radiotherapy in Metastatic Breast Cancer
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|ClinicalTrials.gov Identifier: NCT02538471|
Recruitment Status : Active, not recruiting
First Posted : September 2, 2015
Last Update Posted : February 28, 2018
Patients with metastatic breast cancer receiving at least one single agent chemotherapy and demonstrating stable disease or disease progression at two consecutive clinical/radiological assessments (at an interval of at least 2 weeks).
Transforming growth factor-beta (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.
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Breast Cancer||Radiation: Radiation therapy Drug: Study Drug||Phase 2|
Transforming growth factor-beta (TGFβ) is a pleiotropic cytokine which belongs to a superfamily of ligands, including bone morphogenetic proteins and activins [1-5]. Under normal conditions, members of the TGFβ family maintain homeostasis in many organ systems. In normal and non-cancerous cells, TGFβ limits the growth of epithelial, endothelial, neuronal, and hematopoietic cell lineages through anti-proliferative and apoptotic responses. In addition, TGFβ exerts potent effects that influence immune function, cell proliferation/ functional differentiation, cell adhesion, extracellular matrix production, cell motility, angiogenesis, and cytokine production. TGFβ has been implicated as an important factor in the growth, progression, and metastatic potential of advanced cancers. Although TGFβ has been shown to suppress the growth of epithelial cells in the early stages of tumor development (premalignant conditions), the effect on advanced cancers is more complex [1, 5-6]. Increased production of TGFβ has been found in many neoplasms such as breast, prostate, gastric, renal, and epidermal carcinomas, and elevated plasma TGFβ levels in patients have been correlated with advanced disease, metastases, and lower survival rates [7-13]. In these later stage cancers, TGFβ induced growth suppression is lost, and instead, TGFβ promotes tumor growth and metastasis.
Eli Lilly has developed and produced a Transforming Growth Factor-beta (TGF-β) receptor type-1 kinase inhibitor. LY2157299 monohydrate (LY2157299) is a small molecule that inhibits the TGF-β receptor type 1 kinase activity. LY2157299 was developed to investigate its activity in patients with glioblastoma where TGF-β has been demonstrated to play a specific role in tumor progression. In addition, LY2157299 was investigated in other patient populations, either as a stand-alone therapy or in combination with standard anti-tumor treatment regimens for indications including hepatocellular carcinoma and pancreatic cancer. Future investigations include indications with likely TGF-β associated pathway activation, such as melanoma, breast and prostate cancer as well as hematologic malignancies.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||28 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||LY2157299 Monohydrate (LY2157299) and Radiotherapy in Metastatic Breast Cancer|
|Study Start Date :||August 2015|
|Estimated Primary Completion Date :||December 2018|
|Estimated Study Completion Date :||August 2019|
Experimental: Arm 1 - Study Drug & Radiation therapy
Study Drug: Enrolled patients will receive 300 mg/day of LY2157299. LY2157299 will be administered as an oral drug tablet.
The study drug will be administered orally on a 28-day cycle (1 cycle=28 days), every 2 weeks, or 14 days on / 14 days off. Blood samples will be obtained at baseline, and weeks 2, 6 and 15 for immune monitoring.
Radiation therapy : Patients will receive Radiation therapy to a metastatic site at a dose of 7.5 Gy, given consecutively on days 1, 3 and 5, during Week 1 of their treatment.
Radiation: Radiation therapy
Imaging by PET/CT will be performed at baseline, 5 weeks and 15 weeks. The chosen metastatic sites will receive conformal external beam radiation 7.5 Gy/fraction x 3, to a total of 22.5 Gy over the course of one week.
Other Name: Radiation
Drug: Study Drug
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) .
Other Name: Study Drug - oral
- Percentage of Participants with Adverse Events [ Time Frame: 16 weeks ]Patients who have received at least one 14 days cycle of the study drug will be followed for toxicity (lack of grade 4 toxicity- primary safety end point). Physical exam (including labs) will be performed every 2 weeks while on the study. Patients will be followed with follow-up visits monthly for the first three months after completing therapy then annually for 5 years. Adverse Events will be monitored throughout the course of the study using the NCI CTCAE vers. 4.0.
- to determine if treatment with LY2157299 and localized Radiation therapy to a metastatic site causes the non-irradiated tumor lesions to regress. (Abscopal effect) [ Time Frame: 16 weeks ]To determine if treatment with TGFΒ receptor I kinase inhibitor LY2157299 and localized RT achieves an abscopal tumor regression
- to estimate the local tumor regression response rates among patients [ Time Frame: 25 weeks ]to estimate the local response rate of combining TGFΒ receptor I kinase inhibitor LY2157299 and local radiotherapy
- to determine the function of T regulatory cells in generating anti-tumor responses in metastatic breast cancer [ Time Frame: 2 years ]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
- to determine if combination of LY2157299 and Radiotherapy enhances tumor specific immunity [ Time Frame: 2 years ]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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02538471
|United States, New York|
|Weill Cornell Medical College|
|New York, New York, United States, 10065|
|Principal Investigator:||Silvia Formenti, M.D||Weill Medical College of Cornell University|