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LILY 1312   |   12-315
A Phase II Study of LY2157299 Monohydrate Monotherapy of LY2157299 Monohydrate plus Lomustine Therapy compared to Lumustine Monotherapy in Patients with Recurrent Glioblastoma

Main Campus
Phase 2

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  1. Primary Objective
    • To compare the overall survival (OS) distributions between LY2157299 plus lomustine therapy and lomustine plus placebo therapy (control arm) in patients who have relapsed or have progressive GB after first-line treatment with chemoradiation.
  2. Secondary Objectives
    • Pharmacokinetic: To determine the population plasma PK of LY2157299
    • Safety: To provide additional safety information on LY2157299 monotherapy and LY2157299 plus lomustine therapy and to evaluate the safety of LY2157299 monotherapy and LY2157299 plus lomustine therapy relative to lomustine plus placebo therapy
    • Pharmacodynamic- prognostic and predictive marker assessment:
      • To investigate in tumor tissue, biomarkers associated with tumor growth and the TGF-B signaling pathway and its association with clinical responses (pSMAD and other TGF-B-related biomarkers, O6-MGMT promoter status, or other relative tumor genetic information (eg, IDH1 mutation))
      • To determine serum/plasma tumor markers and secreted proteins (eg, S100B, lactate dehydrogenase [LDH], TGF-B, PF4) and their association with clinical responses
      • To determine T cell biomarker responses, including T regulatory cell counts (eg, CD4 + CD25 + FoxP3 + T cells) and their association with clinical responses
    • Efficacy:
      • To estimate the HR from their OS distributions between: lomustine plus placebo therapy and LY2157299 monotherapy and LY2157299 plus lomustine therapy and LY2157299 monotherapy
      • To estimate PFS distributions for each treatment arm and estimate additional parameters from both the OS distributions and PFS distributions for each treatment arm (such as median OS and PFS, OS and PFS rates at 6, 9, and 12 months)
      • To estimate tumor response rate based on Response Assessment in Neuro-Oncology (RANO) criteria for each treatment arm
    • Health Outcomes: To assess patient-reported symptoms using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) and assess neurocognitive function using the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test Parts A and B, and Controlled Oral Word Association (COWA) for each treatment arm

Inclusion Criteria
  1. Histologically confirmed diagnosis of relapsed intracranial GB (WHO Grade IV; including gliosarcomas). Patients may be entered based on local pathology from the original diagnostic tumor specimen. Patients who have secondary GBs will also be eligible for this trial. To confirm the original diagnosis for all patients, the original diagnostic tumor specimen must be made available for a central pathology review (this will be returned to the original pathology laboratory).
  2. Patients must have evidence of tumor progression as determined by RANO criteria (see Attachment 5) following standard chemoradiation (Stupp protocol).
    • Magnetic resonance imaging (MRI) must be performed within 14 days prior to enrollment, and patients who are receiving steroids must be stable for at least 5 days prior to imaging. If the steroid dose is increased between the date of imaging and enrollment, a new baseline MRI is required. An MRI must be used throughout the period of study treatment for tumor measurement.
    • Patients must have completed only 1 prior course of radiation therapy and must have experienced an interval of ≥ 12 weeks from the completion of radiation therapy to study entry.
    • Patients may have received 1 prior TMZ-based chemotherapy regimen: chemotherapy treatment with concurrent radiotherapy or chemotherapy treatment in the adjuvant setting will each be considered 1 regimen.
    • Patients must have experienced an interval of no less than 30 days from the last day of receiving a chemotherapy treatment prior to receiving study therapy (for biologics and targeted agents for at least 14 days) or shorter depending on their known PK plasma half-life).
  3. Patients may have undergone prior surgical resection and will be eligible if the following conditions apply:
    • Patients must have recovered from the effects of surgery.
    • Evaluable or measurable disease must be present (RANO criteria). To adequately assess the extent of residual disease postoperatively, MRI should be done:
      • In the immediate postoperative < 72 hours. NOTE: if the 72-hour scan is performed more than 14 days prior to enrollment, the scan needs to be repeated. An optimal baseline scan is done 48 hours after surgery
      • OR
      • In the postoperative ( > 4 weeks postoperatively and < 14 days of enrollment). For patients receiving steroids, they must be on stable treatment for at least 5 days. NOTE: If the steroid use is increased between the date of imaging and enrollment, a new baseline MRI is required on a stable steroid dosage of at least 5 days duration
  4. Have available tumor tissue (mandatory) for additional prognostic and predictive biomarker evaluation (from initial pathological diagnosis tissueand/or from subsequent tumor tissues).
  5. Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. See Attachment 4.
  6. Have discontinued all previous treatments for cancer excluding palliative treatments and recovered from the acute effects of therapy (given the toxicity profile, mitomycin-C has to be discontinued at least 42 days and all other chemotherapies 30 days from last administration or for biologics and targeted agents for at least 14 days), or shorter depending on their known PK plasma half-life. At the discretion of the investigator, hormone-refractory prostate cancer patients who are stable on gonadotropin-releasing hormone (GnRH) agonist therapy and breast cancer patients who are stable on antiestrogen therapy (for example, an aromatase inhibitor) may have that treatment continued while they are enrolled in this study.
  7. Have adequate organ function, including:
    • Adequate bone marrow reserve: absolute neutrophil count (ANC). 1.5 x 109/L, platelet count [] 100 x 109/L, and hemoglobin [] 9 g/dL (6.21 mmol/L)
    • Hepatic: total bilirubin [] 2 times the upper limit of normal (ULN); alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) [] 3 x ULN
    • Renal: serum creatinine [] 1.5 times ULN
    • Eligibility for hemoglobin may be reached by transfusion. Patients with hemoglobin > 8 g/dL but < 9 g/dL may receive erythrocyte transfusions to achieve a hemoglobin level ≥ 9 g/dL. Initial treatment must not begin until two days after the erythrocyte transfusion and after the confirmation of hemoglobin level ≥ 9 g/dL.
    • NOTE: Small changes from the outlined laboratory values, which are a result of biological or laboratory equipment variability as evidenced by historical values, will be deemed as consistent with the protocol-requirements provided that they are isolated values, are transient, and are not reflective of a medical condition. Repeat laboratory/hematological tests should be done prior to dosing the patient on Cycle 1 Day 1.
  8. Are males or females at least 18 years old at the time of screening.
    • Male patients: agree to use a reliable method of birth control during the study and for at least 12 weeks following last dose of study drug or country requirements, whichever is longer.
  9. Female patients:
    • are women of child-bearing potential who test negative for pregnancy at the time of enrollment based on a urine pregnancy test and agree to use a reliable method of birth control during the study and for 3 months following the last dose of the investigational product.
    • are postmenopausal women, defined as: at least 6 weeks post surgical bilateral oophorectomy with or without hysterectomy, confirmed by medical history. OR spontaneous amenorrhea for at least 12 months, not induced by a medical condition such as anorexia nervosa and not taking medications during the amenorrhea that induced the amenorrhea (for example, oral contraceptives, hormones, gonadotropin releasing hormone, antiestrogens, selective estrogen receptor modulators, or chemotherapy). OR spontaneous amenorrhea 6 to 12 months and a follicle-stimulating hormone (FSH) level greater than 40 mIU/mL.
  10. Have given written informed consent/assent prior to any study-specific procedures.
  11. Are able to swallow capsules (lomustine) and tablets (LY2157299/placebo).

Exclusion Criteria
  1. Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product (including vascular endothelial growth factor receptor [VEGF-R] inhibitors) or non-approved use of a drug or device (other than the study drug/device used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
  2. Have previously completed or withdrawn from this study or any other study investigating LY2157299.
  3. Have 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 (NYHA) Class III/IV congestive heart failure, or uncontrolled hypertension.
    • Have documented major electrocardiogram (ECG) abnormalities which are not controlled by medical treatments, for example, symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree atrioventricular block, bundle branch blocks, ventricular hypertrophy, or recent myocardial infarction.
    • Have major abnormalities documented by ECHO with Doppler (for example, moderate or severe heart valve function defect and/or left ventricular ejection fraction [LVEF] < 50%, evaluation based on the institutional lower limit of normal). For additional details, refer to ECHO protocol (Attachment 6).
    • 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 chest computed tomography [CT] scan with contrast).
  4. Received prior nitrosourea (including lomustine or Gliadel/local carmustine) therapy
  5. Received prior bevacizumab as part of a first-line treatment for GB (if treatment was concluded 12 months prior to enrollment, the patient may be eligible to participate in the trial).
  6. Have a serious concomitant systemic disorder (for example, active infection including human immunodeficiency virus [HIV]) that, in the opinion of the investigator, would compromise the patient�s ability to adhere to the protocol.
  7. Have current acute or chronic myelogenous leukemia.
  8. Have a second primary malignancy that, in the judgment of the investigator and sponsor, may affect the interpretation of results (eg, slowly progressing tumors that in the past 3 years have shown an accelerated growth and are resistant to other treatments; for breast and prostate cancer patients see inclusion criterion [6]).
  9. Are pregnant or breast-feeding women.
  10. Are unwilling or unable to participate in the study.

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