Clinical Trials /

LY2157299 Monohydrate (LY2157299) and Radiotherapy in Metastatic Breast Cancer

NCT02538471

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">LY2157299</span> Monohydrate (<span class="go-doc-concept go-doc-intervention">LY2157299</span>) and <span class="go-doc-concept go-doc-intervention">Radiotherapy</span> in Metastatic <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • Brief Title: LY2157299 Monohydrate (LY2157299) and Radiotherapy in Metastatic Breast Cancer
  • Official Title: LY2157299 Monohydrate (LY2157299) and Radiotherapy in Metastatic Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02538471

    ORG ID: 1505016222

    Trial Conditions

    Metastatic Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Study Drug Study Drug - oral Arm 1 - Study Drug & Radiation therapy

    Trial Purpose

    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 (TGF) 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 (TGF) 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 TGF family maintain homeostasis in many organ systems. In
    normal and non-cancerous cells, TGF limits the growth of epithelial, endothelial, neuronal,
    and hematopoietic cell lineages through anti-proliferative and apoptotic responses. In
    addition, TGF exerts potent effects that influence immune function, cell proliferation/
    functional differentiation, cell adhesion, extracellular matrix production, cell motility,
    angiogenesis, and cytokine production. TGF has been implicated as an important factor in
    the growth, progression, and metastatic potential of advanced cancers. Although TGF 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 TGF has been found in many neoplasms such as breast,
    prostate, gastric, renal, and epidermal carcinomas, and elevated plasma TGF levels in
    patients have been correlated with advanced disease, metastases, and lower survival rates
    [7-13]. In these later stage cancers, TGF induced growth suppression is lost, and instead,
    TGF promotes tumor growth and metastasis.

    Eli Lilly has developed and produced a Transforming Growth Factor-beta (TGF-) receptor
    type-1 kinase inhibitor. LY2157299 monohydrate (LY2157299) is a small molecule that inhibits
    the TGF- receptor type 1 kinase activity. LY2157299 was developed to investigate its
    activity in patients with glioblastoma where TGF- 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- associated pathway activation,
    such as melanoma, breast and prostate cancer as well as hematologic malignancies.

    Trial Arms

    Name Type Description Interventions
    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. Study Drug

    Eligibility Criteria

    Inclusion Criteria :

    1. Biopsy proven breast carcinoma which is persistent and metastatic or recurrent and
    metastatic.

    2. Patients must have failed at least one line of chemotherapy for metastatic disease.

    3. 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

    4. 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

    5. 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.

    6. Patient 18 years of age. Patient life expectancy > 6 months. Eastern cooperative
    group (ECOG) of 0 or 1

    7. Adequate organ function including:

    1. Marrow: Hemoglobin >= 10.0 g/dL, absolute neutrophil count (ANC) >=1,500/mm3,
    and platelets >=100,000/mm3.

    2. 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.

    3. Renal: Estimated or measured creatinine clearance >= 60 mL/min.

    4. Other: Prothrombin time (PT) and partial thromboplastin time (PTT) < ULN.

    8. 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.

    9. 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.

    Exclusion Criteria :

    1. 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.

    2. Concurrent cancer therapy is not permitted.

    3. 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).

    4. History of ascites or pleural effusions, unless successfully treated.

    5. Patients with an organ transplant, including those that have received an allogeneic
    bone marrow transplant.

    6. Patients on immunosuppressive therapy including:

    1. 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).

    2. Patients receiving cyclosporine A, tacrolimus, or sirolimus are not eligible for
    this study.

    7. 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).

    8. Patients with moderate or severe cardiac disease:

    1. 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.

    2. 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).

    3. 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.

    4. 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).

    9. 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.

    10. Patients with a remote history of asthma or active mild asthma may participate.

    11. Active infection, including unexplained fever (temperature > 38.5 deg.C).

    12. Systemic autoimmune disease (e.g., systemic lupus erythematosus, active rheumatoid
    arthritis, Marfan Syndrome, etc.).

    13. A known allergy to any component of LY2157299.

    14. 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:

    1. 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).

    2. 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

    15. Pregnant or nursing women, due to the unknown effects ofLY2157299 on the developing
    fetus or newborn infant.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: 90 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Percentage of Participants with Adverse Events

    to determine if treatment with LY2157299 and localized Radiation therapy to a metastatic site causes the non-irradiated tumor lesions to regress. (Abscopal effect)

    Secondary Outcome Measures

    to estimate the local tumor regression response rates among patients

    to determine the function of T regulatory cells in generating anti-tumor responses in metastatic breast cancer

    to determine if combination of LY2157299 and Radiotherapy enhances tumor specific immunity

    Trial Keywords