H9H-MC-JBAL

Eli Lilly and Company

Lilly Corporate Center, Indianapolis, IN, United States, 46285

Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-CTLilly, EU_Lilly_Clinical_Trials@lilly.com

Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-285-4559, EU_Lilly_Clinical_Trials@lilly.com

No

No

No

Final

10 Oct 2024

No

Yes

10 Oct 2024

No

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

This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.

26 Apr 2012

No

No

Netherlands: 2

Poland: 2

Spain: 14

Belgium: 14

France: 35

Germany: 16

Italy: 30

Canada: 4

United States: 21

Australia: 20

158

113

0

0

0

0

0

0

122

36

0

Overall Study (overall period)

Randomised - controlled

Yes

Galunisertib

LY2157299 monohydrate

Tablet

Oral use

Participants received Galunisertib 300 milligrams (mg) orally twice daily (BID) for 14 days, followed by 14 days of rest in a 28-day cycle.

Galunisertib

LY2157299 monohydrate

Tablet

Oral use

Participants received Galunisertib 300 milligrams (mg) orally twice daily (BID) for 14 days, followed by 14 days of rest in a 28-day cycle.

Lomustine

Capsule

Oral use

Participants received a first dose of Lomustine at 100 milligrams per square meter (mg/m²) administered orally. Thereafter, starting with the second dose, Lomustine was administered orally once every 6 weeks at 100-130 mg/m², at the discretion of the investigator.

Lomustine

Capsule

Oral use

Participants received a first dose of Lomustine at 100 mg/m² administered orally. Thereafter, starting with the second dose, Lomustine was administered orally once every 6 weeks at 100-130 mg/m², at the discretion of the investigator.

Placebo

Galunisertib-matched Placebo

Tablet

Oral use

Participants received Galunisertib-matched Placebo orally BID for 14 days, followed by 14 days of rest in a 28-day cycle.

Arm A: Galunisertib

Arm B: Galunisertib + Lomustine

Arm C: Lomustine + Placebo

Arm A: Galunisertib

Arm B: Galunisertib + Lomustine

Arm C: Lomustine + Placebo

Arm A: Galunisertib and Arm B: Galunisertib + Lomustine

Arm A: Galunisertib: Participants received Galunisertib 300 mg orally BID for 14 days, followed by 14 days of rest in a 28-day cycle until disease progression, death, or discontinuation criteria were met. Arm B: Galunisertib + Lomustine: Participants received Galunisertib 300 mg orally BID for 14 days, followed by 14 days of rest in a 28-day cycle, plus received a first dose of Lomustine at 100 mg/m² administered orally. Thereafter, starting with the second dose, Lomustine was administered orally once every 6 weeks at 100-130 mg/m², at the discretion of the investigator, until disease progression, death, or discontinuation criteria were met.

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. APD:All randomized participants who received at least one dose of study drug (including the censored participants). Number of participants censored in Arm A: Galunisertib = 9; Arm B: Galunisertib + Lomustine = 8; and Arm C: Lomustine + Placebo = 6.

Primary

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

The Bayesian analyses below include credible intervals rather than confidence intervals for the hazard ratios.The posterior probability treatment difference is 0.6158.

Arm A: Galunisertib v Arm C: Lomustine + Placebo

79

Pre-specified

0.9336

2-sided

The Bayesian analyses below include credible intervals rather than confidence intervals for the hazard ratios.The posterior probability treatment difference is 0.2628.

Arm B: Galunisertib + Lomustine v Arm C: Lomustine + Placebo

119

Pre-specified

1.129

2-sided

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. APD:All randomized participants who received at least one dose of study drug (including the censored participants). Number of participants censored in Arm A: Galunisertib = 7; Arm B: Galunisertib + Lomustine = 8; and Arm C: Lomustine + Placebo = 4.

Secondary

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

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. APD:All randomized participants who received at least 1 dose of study drug.

Secondary

Randomization until measured progressive disease (Up To 19 Months)

The absorption rate constant (Ka) of Galunisertib was estimated using PopPK modeling based on plasma concentration-time data collected during Cycle 1. A two-compartment model with first-order absorption 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 Ka values were derived from model-estimated parameters using all available PK timepoints.The reported outcome is the mean of these individual Ka estimates across both treatment arms (Arm A: Galunisertib; Arm B: Galunisertib + Lomustine). APD:All randomized participants who received ≥1 dose of Galunisertib (Arm A and Arm B) and had evaluable PK data were included in the analysis. As prespecified in the statistical analysis plan, PK analyses of Galunisertib exposure parameters were conducted using data combined from both arms.

Secondary

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

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). APD:All randomized participants who received ≥1 dose of Galunisertib (Arm A and Arm B) and had evaluable PK data were included in the analysis. As prespecified in the statistical analysis plan, PK analyses of Galunisertib exposure parameters were conducted using data combined from both arms.

Secondary

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

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). APD: All randomized participants who received ≥1 dose of Galunisertib (Arm A and Arm B) and had evaluable PK data were included in the analysis. As prespecified in the statistical analysis plan, PK analyses of Galunisertib exposure parameters were conducted using data combined from both arms.

Secondary

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

The HVLT-R was a validated neurocognitive function assessment used to evaluate verbal learning and memory. The HVLT-R consisted of: Three Learning Trials: Participants were presented with a list of 12 words (from three semantic categories) and were asked to recall them. Delayed Recall Trial: Conducted 20-25 minutes after the third learning trial to assess memory retention. Delayed Recognition Trial: Participants identified previously presented words from a list that included distractors. Scoring Components: Total Recall Score (0-36): Sum of correctly recalled words across the three learning trials. Delayed Recall Score (0-12): Number of correct words recalled after the delay. Recognition Discrimination Index Score: Calculated as the number of true positives (correctly identified words) minus false positives (incorrectly identified words). For each of the 3 reported scores, higher scores = better neurocognitive performance; lower scores = decline.

Secondary

Baseline, Month 20 (APD: All randomized participants who received ≥1 dose and had baseline and ≥1 post-baseline measurement for this outcome).

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."

Secondary

Baseline, Month 21 (APD: All randomized participants who received ≥1 dose and had baseline and ≥1 post-baseline measurement for this outcome).

Baseline Up to 11 years 4 months

Safety Analysis Population includes all randomized participants who received ≥1 dose of study drug, analyzed by actual treatment received. 1 participant in Arm B received only Galunisertib (no Lomustine) Thus, Arm A = 40 and Arm B=78. 1 participant in Arm C received only placebo thus Arm C: Lomustine + Placebo = 39; Arm C: Placebo Alone = 1.

27.1

Arm A: Galunisertib and Arm B: Galunisertib (Monotherapy)

Arm B: Galunisertib + Lomustine

Arm C: Lomustine + Placebo

Arm C: Lomustine + Placebo (Placebo Alone)