A Study in Recurrent Glioblastoma (GB)

Eli Lilly and Company158 enrolled

Overview

The purpose of the study is to see whether treatment with LY2157299 on its own, LY2157299 plus lomustine therapy or lomustine plus placebo can help participants with brain cancer

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

158

Conditions

Glioblastoma

Interventions

GalunisertibDRUG

Administered orally

LomustineDRUG

Administered orally

PlaceboDRUG

Administered orally

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Histological confirmed diagnosis of relapsed intracranial GB * Progressive Disease (PD) following standard chemoradiation * Prior surgical resection allowed * Performance status Eastern Cooperative Oncology Group (ECOG) 0 or 1 * Adequate hematologic, hepatic and renal function * Discontinued all prior cancer treatments for cancer \& recovered from the acute effects of therapy * Tumor specimen must be available for a central pathology review and prognostic and predictive biomarker evaluation Exclusion Criteria: * Moderate or severe heart disease based on New York Heart Association (NYHA) criteria * Prior nitrosurea therapy (including lomustine or Gliadel) * Prior bevacizumab as 1st line treatment for GB (if treatment was concluded 12 months prior to enrollment, the patient may be eligible to participate in the trial) * Current acute or chronic myelogenous leukemia * Second primary malignancy that may affect the interpretation of results * Serious concomitant systemic disorder

Locations (29)

Outcomes

Primary Outcomes

Overall Survival (OS)

OS is defined as the time from the date of randomization until death from any cause. For participants not known to have died by the data-inclusion cutoff date, OS is censored at the last date they were known to be alive.

Time frame: Randomization to Date of Death from Any Cause (Up To 20.5 Months)

Secondary Outcomes

Progression Free Survival (PFS)

PFS was defined as the time from randomization to the date of the first observation of objective disease progression or death from any cause, whichever occurred first. Participants known to be alive and without disease progression were censored at the date of their last objective progression-free disease assessment prior to the initiation of any subsequent systemic anticancer therapy.

Time frame: Randomization to Objective Progression or Death Due to Any Cause (Up To 19 Months)

Percentage of Participants With Tumour Response

Tumour response was assessed using Response Assessment in Neuro-Oncology (RANO) criteria. Responses included Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD). CR required disappearance of all enhancing lesions, no new lesions, stable or improved non-enhancing lesions, and no corticosteroid use. PR was defined as ≥50% reduction in enhancing lesion size, no new lesions, stable or improved non-enhancing lesions, and stable or reduced corticosteroid use. SD indicated no significant change in lesion size or clinical status. PD was defined as ≥25% increase in lesion size, new lesions, or clinical deterioration. Percentage of participants with tumor response is defined as the percentage of participants who achieved these tumor responses based on RANO criteria.Participants whose tumor response could not be assessed due to inadequate imaging data were categorized as 'Unknown'.

Time frame: Randomization until measured progressive disease (Up To 19 Months)

Population Pharmacokinetics (PopPK): Absorption Rate Constant of Galunisertib (Arm A: Galunisertib and Arm B: Galunisertib + Lomustine)

Data from ClinicalTrials.gov

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For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Birmingham, Alabama, United States

La Jolla, California, United States

San Francisco, California, United States

Cleveland, Ohio, United States

Dallas, Texas, United States

St Leonards, New South Wales, Australia

Heidelberg, Victoria, Australia

Parkville, Victoria, Australia

Edegem, Belgium

Ghent, Belgium

...and 19 more locations

Population Pharmacokinetics (PopPK): Mean Steady State Apparent Volume of Distribution (Vss) of Galunisertib (Arm A: Galunisertib and Arm B: Galunisertib + Lomustine)

The Vss at steady state of Galunisertib was estimated using PopPK modeling based on plasma concentration-time data collected during Cycle 1.A two-compartment model was applied using nonlinear mixed-effects modeling. Samples were collected at the following time points: Cycle 1 Day 1: Predose, 0.5-2 hours (h), 3.5-5 h, and 48 h post-dose; Day 14: Predose, 0.5-2 h, 3.5-5 h, 24 h, and 48 h post last dose. Individual participant Vss values were derived from model-estimated parameters using all available PK timepoints. The reported outcome is the mean of individual Vss estimates across both treatment arms (Arm A: Galunisertib; Arm B: Galunisertib + Lomustine).

Time frame: Cycle (C) 1: Day (D)1: Predose, 0.5-2 hours (h), 3.5-5 h, and 48 h post-dose; Day 14: Predose, 0.5-2 h, 3.5-5 h, 24 h, and 48 h post last dose

Population Pharmacokinetics (PopPK): Mean Population Clearance of Galunisertib (Arm A: Galunisertib and Arm B: Galunisertib + Lomustine)

The apparent clearance (CL/F) of Galunisertib was estimated using PopPK modeling based on plasma concentration-time data collected during Cycle 1. A two-compartment model was applied using nonlinear mixed-effects modeling. Samples were collected at the following time points: Cycle 1 Day 1: Predose, 0.5-2 hours (h), 3.5-5 h, and 48 h post-dose; Day 14: Predose, 0.5-2 h, 3.5-5 h, 24 h, and 48 h post last dose. Individual participant CL/F values were derived from model-estimated parameters using all available PK timepoints. The reported outcome is the mean of these individual CL/F estimates across both treatment arms (Arm A: Galunisertib; Arm B: Galunisertib + Lomustine).

Time frame: Cycle (C) 1: Day (D)1: Predose, 0.5-2 hours (h), 3.5-5 h, and 48 h post-dose; Day 14: Predose, 0.5-2 h, 3.5-5 h, 24 h, and 48 h post last dose

Change From Baseline in Neurocognitive Function Using Hopkins Verbal Learning Test-Revised (HVLT-R)

The Hopkins Verbal Learning Test-Revised comprises: * 3 Learning Trials: Participants were presented with a list of 12 words (from 3 semantic categories) and were asked to recall them to test verbal learning and memory. * Delayed Recall Trial: Conducted 20-25 minutes after the 3rd learning trial to test memory retention. * Delayed Recognition Trial: Participants identified previously presented words from a list that included 12 distractors to test recognition discrimination. Scoring Components: * Total Recall Score (0-36): Sum of correctly recalled words across the 3 learning trials. * Delayed Recall Score (0-12): Number of correct words recalled after the delay. * Recognition Discrimination Index Score (+12 to -12): Calculated as the number of true positives (correctly identified words) minus false positives (incorrectly identified words, i.e., distractors). For each of the 3 reported scores, higher scores = better neurocognitive performance; lower scores = decline.

Time frame: Baseline, Month 20

Change From Baseline in MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom and Interference Severity Scores: (Brain Tumor Symptoms, Core Symptoms, Interference Symptoms)

The MDASI-BT assesses the severity of multiple brain tumor-related symptoms and the impact of these symptoms on daily functioning in the last 24 hours. It includes: * 13 core symptoms measuring severity of pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, memory problems, lack of appetite, drowsiness, dry mouth, sadness, vomiting, and numbness/tingling, rated 0-10, where 0 = "not present" and 10 = "as bad as you can imagine." * 9 brain tumor-specific symptoms assess severity of difficulty speaking, weakness, seizures, difficulty understanding, vision changes, appearance changes, bowel pattern changes, concentration problems, and irritability, rated 0-10, where 0 = "not present" and 10 = "as bad as you can imagine." * 6 interference items assess impact on general activity, mood, work, relations, walking, and enjoyment of life, rated 0-10, where 0 = "did not interfere" and 10 = "interfered completely."

Time frame: Baseline, Month 21