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Report for Clinical Trial NCT01339052

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Phase II Study of BKM 120 for Patients With Recurrent Glioblastoma and Activated PI3K Pathway

BKM120 is a newly discovered drug that has been used in other research studies. Information from those other research studies suggests that BKM120 may help to slow or stop the growth of malignant gliomas. The purpose of this study is to see how well BKM120 works in patients with malignant gliomas. Patients on this study will be treated in two groups: patients who are going to receive surgery and those who will not receive surgery. This study is trying to determine how effective BKM120 is in stopping cancer cells from growing. For patients receiving surgery the research will also try to determine if an effective level of BKM120 can penetrate the brain before surgery.

NCT01339052 Glioblastoma
MeSH:Glioblastoma
HPO:Glioblastoma multiforme

2 Interventions

Name: BKM120

Type: Drug
Group Labels: 2

Cohort 1: Surgical subjects Cohort 2: Non-surgical subjects

Name: Surgery

Description: Surgery
Type: Procedure
Group Labels: 1

Cohort 1: Surgical subjects


Primary Outcomes

Description: pAKT response was determined by pathologist-performed semi-quantitative IHC scoring for pAKT using previously established methods for glioblastoma (GBM) patients. Sample staining scored for intensity on a 0-2+ scale (0 none, 1+ weak positive, 2+ strong positive). Change in pAKT IHC score was the difference in score from baseline to surgery. Participants were classified into 3 groups: a reduction of staining score of one degree or more (considered a response), an increase in score and no change in score.

Measure: Change in pAKT (S473) Immunohistochemistry (IHC) Score From Baseline to Surgery [Cohort 1]

Time: Samples were collected at baseline and at surgery (resected surgical tumor specimen) which occurred after up to 12 days of BKM120 treatment.

Description: PFS6 is the proportion of participants remaining alive and progression-free at 6-months from cycle 1 day 1 of BKM120 treatment. Progressive disease is defined using RANO (Response Assessment in Neuro-Oncology) criteria (Wen et al JCO 2010), which takes modified Macdonald Criteria and adds assessment of non-enhancing lesions. Per RANO, progressive disease (PD) is defined either as > 25% increase in sum of the products of perpendicular diameters of enhancing lesions on stable or increasing doses of corticosteroids, or one or more of the of the following: 1) Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids steroids not due to co-morbid events; 2) Any new lesion; 3) Clear clinical deterioration not attributable to other causes apart from the tumor; or 4) Failure to return for evaluation due to death or deteriorating condition.

Measure: 6-Month Progression-Free Survival (PFS6) [Cohort 2]

Time: Participants were assessed radiologically every other cycle on treatment; Relevant for this outcome is up to month 6 evaluation.

Description: Levels of BKM120 were determined by liquid chromatography coupled with tandem mass spectrometry. BKM120 tumor-to-plasma ratio at time of surgery was calculated based on these levels.

Measure: BKM120 Brain-to-Plasma Ratio at Time of Surgery [Cohort 1]

Time: Samples were collected at surgery (surgical tumor specimen and plasma sample) which occurred after up to 12 days of BKM120 treatment.

Description: Levels of BKM120 were determined by liquid chromatography coupled with tandem mass spectrometry.

Measure: BKM120 Tumor Tissue Concentration at Time of Surgery [Cohort 1]

Time: Samples were collected at surgery (resected surgical tumor specimen) which occurred after up to 12 days of BKM120 treatment.

Description: Levels of BKM120 were determined by liquid chromatography coupled with tandem mass spectrometry.

Measure: BKM120 Plasma Concentration at Time of Surgery [Cohort 1]

Time: Samples were collected at surgery which occurred after up to 12 days of BKM120 treatment.

Secondary Outcomes

Description: Tumor cell proliferation and tumor cell death was using immunohistochemistry for Ki-67 based on established methods. Percent reduction was based on Ki-67 levels at baseline and at surgery.

Measure: % Ki-67 Reduction Using Immunohistochemistry (IHC) [Cohort 1]

Time: Samples were collected at baseline (archival tumor specimen) and at surgery (surgical tumor specimen) which occurred after up to 12 days of BTK120 treatment.

Description: Radiographic response was based on RANO (Response Assessment in Neuro-Oncology) criteria. Per RANO, complete response (CR): 1) Complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks, 2) No new lesions, 3) All lesions assessed using the same techniques as baseline, 4) No steroid use (or on physiologic replacement doses only), 5) Stable or improved non-enhancing (T2/FLAIR) lesions and 6) Stable or improved clinically; partial response (PR): 1) >/= 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions (sum LD) sustained for at least 4 weeks and 2) No progression; progressive disease (PD): 1) > 25% increase sum LD and/or 2) significant increase in T2/FLAIR, 3) any new lesion, 4) clear clinical deterioration; stable disease (SD): none of the above.

Measure: Radiographic Response [Cohort 2]

Time: Participants were assessed radiologically every other cycle on treatment. Cohort 2 participants were on treatment up to 9.2 months.

Description: Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. NOTE: This outcome measure was previously titled: "Investigate Pharmacokinetics of BKM120 in This Population by Comparing Maximum Plasma Concentrations (Cmax) From Day 1 to Day 8"

Measure: Maximum Observed Plasma Concentrations (Cmax) of BKM120 Day 1 and Day 8 [Cohort 1]

Time: On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Description: Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. The accumulation ratio is day 8/day 1.

Measure: Cmax Accumulation Ratio of BKM120 Day 1 and Day 8 Ratio [Cohort 1]

Time: On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Description: Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. NOTE: This outcome measure was previously titled: "Investigate Pharmacokinetics of BKM120 in This Population by Comparing the Drug Exposure Area Under the Curve (AUC0-5h) From Day 1 to Day 8"

Measure: Area Under the Concentration Curve From Time 0 to Last Concentration (AUC0-5h) of BKM120 Day 1 and Day 8 [Cohort 1]

Time: On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Description: Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods. The accumulation ratio is day 8/day 1.

Measure: AUC0-5h Accumulation Ratio of BKM120 Day 1 and Day 8 [Cohort 1]

Time: On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Description: Plasma concentrations of BKM120 were analyzed by a validated liquid chromatography-tandem mass spectrometry assay developed by Novartis Pharma AG. Standard Pk parameters were determined using non-compartmental methods.

Measure: Time to Maximum Observed Plasma Concentration (Tmax) of BKM120 Day 1 and Day 8 [Cohort 1]

Time: On days 1 and 8 (+/- 1 day) prior to surgery, 5 blood samples were collected at the following timepoints: pre-dose, and at 0.5, 1.5, 3, and 5 hours post-dose.

Description: Overall survival is defined as the time from date of first dose to death or date last known alive and estimated using Kaplan-Meier (KM) methods.

Measure: Overall Survival (OS) [Cohort 2]

Time: Participants were followed long-term for survival via medical record review. Cohort 2 participants were followed for survival up to 52 months in this study cohort.

Description: PFS is defined as the time from first dose to the earliest documentation of disease progression or death. Participants alive without evidence of PD were censored at the date of last disease assessment. Progressive disease was established based on Response Assessment in Neuro-Oncology (RANO) criteria (Wen et al JCO 2010). See outcome measure #2.

Measure: Progression-Free Survival (PFS) [Cohort 2]

Time: Participants were assessed radiologically every other cycle on treatment and off-treatment via medical record review until death. Cohort 2 participants were followed for progression-free survival up to 12 months in this study cohort.

Description: The percentage of patients who experienced any grade 3-5 treatment-related adverse event based on CTCAEv4 as reported on case report forms.

Measure: Grade 3-5 Treatment-Related Toxicity Rate

Time: Adverse events experienced by participants are collected and reported throughout treatment with study drug (from initiation of study medication until 30 days after the last dose of BKM120), maximum timeframe was 2 years.

Purpose: Treatment

Allocation: Non-Randomized

Parallel Assignment


There is one SNP

SNPs


1 P13K

Exclusion Criteria: - Participants who have received prior treatment with a P13K inhibitor, AKT inhibitor, mTOR inhibitor (e.g. --- P13K ---



HPO Nodes


HPO: