Metastatic Breast CancerPhase 2NCT02538471
LY2157299 Monohydrate (LY2157299) and Radiotherapy in Metastatic Breast Cancer
A Phase 2 study testing Radiation therapy and Study Drug in people with Metastatic Breast Cancer, run by Weill Medical College of Cornell University at 1 site in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Metastatic Breast Cancer
- What is being tested?
- Radiation therapy and Study Drug
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 1 siteUnited States
- Study dates
- 10 Aug 2015to 20 Feb 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Biopsy proven breast carcinoma which is persistent and metastatic or recurrent and metastatic.
- Patients must have failed at least one line of chemotherapy for metastatic disease.
- Patients who are Human epidermal growth factor 2 +(HER2+) as defined by American Society of Clinical Oncology and College of American Pathologists (ASCO CAP) guidelines must have failed all prior therapy known to confer clinical benefit
- Patients must have at least 3 distinct metastatic sites with at least one measurable lesion which is at least 1 cm or larger in largest diameter
- At the time of enrollment, patients must be ≥ 4 weeks since all of the following treatments (and recovered from the toxicity of prior treatment to <= Grade 1, exclusive of alopecia):
- major surgery; radiotherapy; chemotherapy (note: must be ≥ 6 weeks since therapy if treated with a nitrosourea, mitomycin, or monoclonal antibodies such as bevacizumab); immunotherapy; Biotherapy/targeted therapies.
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- Patient ≥ 18 years of age. Patient life expectancy > 6 months. Eastern cooperative group (ECOG) of 0 or 1
- Adequate organ function including:
- Marrow: Hemoglobin >= 10.0 g/dL, absolute neutrophil count (ANC) >=1,500/mm3, and platelets >=100,000/mm3.
- Hepatic: Serum total bilirubin <=1.5 x upper limit of normal (ULN) (Patients with Gilbert's Disease may be included if their total bilirubin is <= 3.0 mg/dL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <= 2.5 x ULN. If the patient has known liver metastases, an ALT and/or AST <= 5 x ULN are allowed.
- Renal: Estimated or measured creatinine clearance >= 60 mL/min.
- Other: Prothrombin time (PT) and partial thromboplastin time (PTT) < ULN.
- Patients must have negative tests (antibody and/or antigen) for hepatitis viruses B and C unless the result is consistent with prior vaccination or prior infection with full recovery.
- Male and female patients of child-producing potential must agree to use effective contraception while enrolled on study and receiving the experimental drug, and for at least 3 months after the last treatment.
Who cannot join
- Patients diagnosed with another malignancy - unless following curative intent therapy, the patient has been disease free for at least 2 years and the probability of recurrence of the prior malignancy is < 5%. Patients with curatively treated early-stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia (CIN) are eligible for this study.
- Concurrent cancer therapy is not permitted.
- Uncontrolled central nervous system (CNS) metastases, meningeal carcinomatosis, malignant seizures, or a disease that either causes or threatens neurologic compromise (e.g., unstable vertebral metastases).
- History of ascites or pleural effusions, unless successfully treated.
- Patients with an organ transplant, including those that have received an allogeneic bone marrow transplant.
- Patients on immunosuppressive therapy including:
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- Systemic corticosteroid therapy for any reason, including replacement therapy for hypoadrenalism. Patients receiving inhaled or topical corticosteroids may participate (if therapy is < 5 days and is limited to systemic steroids as antiemetics).
- Patients receiving cyclosporine A, tacrolimus, or sirolimus are not eligible for this study.
- Use of investigational agents within 4 weeks prior to study enrollment (within 6 weeks if the treatment was with a long-acting agent such as a monoclonal antibody).
- Patients with moderate or severe cardiac disease:
- have the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension.
- have documented major electrocardiogram (ECG) abnormalities (not responding to medical treatments) at the investigator's discretion (for example, symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree atrio ventricular block, complete bundle branch block, ventricular hypertrophy, or recent myocardial infarction).
- have major abnormalities documented by echocardiography (ECHO) with Doppler (for example, moderate or severe heart valve function defect and/or left ventricular ejection fraction <50%, evaluation based on the institutional lower limit of normal). For additional details, refer to ECHO protocol.
- have predisposing conditions that are consistent with development of aneurysms of the ascending aorta or aortic stress (for example, family history of aneurysms, Marfan-Syndrome, bicuspid aortic valve, evidence of damage to the large vessels of the heart documented by computed tomography (CT) scan with contrast).
- B-type Natriuretic Peptide (BNP) above 3 times the baseline value and above the ULN that is sustained consecutive, scheduled blood draws. Troponin I above ULN, high sensitive C-reactive protein (hsCRP) above ULN or Cystatin above ULN.
- Patients with a remote history of asthma or active mild asthma may participate.
- Active infection, including unexplained fever (temperature > 38.5 deg.C).
- Systemic autoimmune disease (e.g., systemic lupus erythematosus, active rheumatoid arthritis, Marfan Syndrome, etc.).
- A known allergy to any component of LY2157299.
- Patients who, in the opinion of the Investigator, have significant medical or psychosocial problems that warrant exclusion. Examples of significant problems include, but are not limited to:
- Other serious non-malignancy-associated medical conditions that may be expected to limit life expectancy or significantly increase the risk of Serious Adverse Events (SAEs).
- Any condition, psychiatric, substance abuse, or otherwise, that, in the opinion of the Investigator, would preclude informed consent, consistent follow-up, or compliance with any aspect of the study
- Pregnant or nursing women, due to the unknown effects ofLY2157299 on the developing fetus or newborn infant.
Trial locations and contacts
1 site in 1 country.
United States1 site
Weill Cornell Medical College
New York, New York, 10065
About this study
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.
Read the detailed description
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.
- Conditions
- Metastatic Breast Cancer
- Being tested
- Radiation therapy, Study Drug
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Radiation therapyRadiation
Also called Radiation
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.
Study DrugDrug
Also called Study Drug - oral
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) .
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 - Study Drug & Radiation therapy | Experimental | 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. Receives: Radiation: Radiation therapy; Drug: Study Drug |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Adverse Events
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.
Measured: until end of study
Number of Participants Non-irradiated Tumor Lesions That Had a Response.
To determine if treatment with TGFΒ receptor I kinase inhibitor LY2157299 and localized RT achieves an abscopal tumor regression
Measured: Until next progression up to 3 years
Secondary outcomes (3)
Number of Participants Who Received Radiation to the Tumor Who Had a Response.
to estimate the local response rate of combining TGFΒ receptor I kinase inhibitor LY2157299 and local radiotherapy
Measured: 25 weeks
Number of Participants Who Had a Change in Their T Regulatory Cell Numbers and Function Over the Course of the Study.
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
Measured: 2 years
Number of Participants With Enhanced Tumor Specific Immunity.
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Sep 2015 (estimated)
- Study start10 Aug 2015
- Primary completion4 Sep 2018
- Study completion20 Feb 2019
Why it stopped: The study was terminated due to lack of patient accrual.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Metastatic Breast CancerStudies of the same condition, open and under way.
- More trials run by Weill Medical College of Cornell UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- Weill Medical College of Cornell University
- Sponsor type
- University, hospital or other
- Collaborators
- University of California, Los Angeles
- Responsible party
- Sponsor
- Investigators
- Silvia Formenti, M.D, Principal investigator, Weill Medical College of Cornell University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02538471
- Sponsor's protocol ID
- 1505016222
- Status last verified
- Nov 2019
- First submitted
- 27 Aug 2015
- Last updated
- 9 Dec 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- LY2157299 Monohydrate (LY2157299) and Radiotherapy in Metastatic Breast Cancer
- ClinicalTrials.gov ID
- NCT02538471
- Acronym / sponsor ID
- 1505016222
- Conditions
- Metastatic Breast Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study was terminated due to lack of patient accrual.
- Enrolment
- 3 participants (actual)
- Lead sponsor
- Weill Medical College of Cornell UniversityUniversity, hospital or other
- Collaborators
- University of California, Los Angeles
- Study start
- 10 Aug 2015 (actual)
- Primary completion
- 4 Sep 2018 (actual)
- Study completion
- 20 Feb 2019 (actual)
- First posted
- 2 Sep 2015 (estimated)
- Results
- Posted 9 Dec 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Arm 1 - Study Drug & Radiation therapy | Experimental | Radiation: Radiation therapy, Drug: Study DrugStudy 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. |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Biopsy proven breast carcinoma which is persistent and metastatic or recurrent and metastatic.
- Patients must have failed at least one line of chemotherapy for metastatic disease.
- Patients who are Human epidermal growth factor 2 +(HER2+) as defined by American Society of Clinical Oncology and College of American Pathologists (ASCO CAP) guidelines must have failed all prior therapy known to confer clinical benefit
- Patients must have at least 3 distinct metastatic sites with at least one measurable lesion which is at least 1 cm or larger in largest diameter
- At the time of enrollment, patients must be ≥ 4 weeks since all of the following treatments (and recovered from the toxicity of prior treatment to <= Grade 1, exclusive of alopecia):
Key exclusion criteria (23 listed)
- Patients diagnosed with another malignancy - unless following curative intent therapy, the patient has been disease free for at least 2 years and the probability of recurrence of the prior malignancy is < 5%. Patients with curatively treated early-stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia (CIN) are eligible for this study.
- Concurrent cancer therapy is not permitted.
- Uncontrolled central nervous system (CNS) metastases, meningeal carcinomatosis, malignant seizures, or a disease that either causes or threatens neurologic compromise (e.g., unstable vertebral metastases).
- History of ascites or pleural effusions, unless successfully treated.
- Patients with an organ transplant, including those that have received an allogeneic bone marrow transplant.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Radiation therapyAlso: RadiationImaging 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. | Radiation | Arm 1 - Study Drug & Radiation therapy |
| Study DrugAlso: Study Drug - oralPatients 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) . | Drug | Arm 1 - Study Drug & Radiation therapy |
Primary outcome
Number of Participants With Adverse Events
Time frame: until end of study
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.
Number of Participants Non-irradiated Tumor Lesions That Had a Response.
Time frame: Until next progression up to 3 years
To determine if treatment with TGFΒ receptor I kinase inhibitor LY2157299 and localized RT achieves an abscopal tumor regression
3 secondary outcomes
Number of Participants Who Received Radiation to the Tumor Who Had a Response.
Time frame: 25 weeks
Number of Participants Who Had a Change in Their T Regulatory Cell Numbers and Function Over the Course of the Study.
Time frame: 2 years
Number of Participants With Enhanced Tumor Specific Immunity.
Time frame: 2 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Dec 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Silvia Formenti, M.D principal investigator
Weill Medical College of Cornell University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Radiation therapy and Study Drug in people with Metastatic Breast Cancer, run by Weill Medical College of Cornell University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 9 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Dec 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Adverse Events (time frame: until end of study). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Dec 2019.