A Phase I Dose Escalation Study of BKM120 With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

Study Overview
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Brief Summary
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This clinical study will assess the doses of BKM120 appropriate for patients with newly diagnosed glioblastoma when given in combination with radiotherapy and temozolomide.

Official Title
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A Phase I, Two-stage, Multi-center, Open Label, Dose-escalation Study of BKM120 in Combination With Adjuvant Temozolomide and With Concomitant Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: BKM120 + temozolomide
* Drug: BKM120 +temozolomide with/without radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is ≥ 18 years of age on the day of consent signature Patient with histologically demonstrated, previously untreated glioblastoma Patient may have received initial treatment for GBM as follows: For patients enrolled into Stage I, they must have received at least 75% of planned radiotherapy (60 Gy) with temozolomide treatment during the concomitant phase have documentation that the patient's absolute neutrophil count (ANC) is ≥ 1.5 x 109/L, platelet count is ≥ 100 x 109/L, and there was no CTC grade 2 or above nonhematological toxicity (except for alopecia, nausea, vomiting) during the concomitant phase treatment be within ≥ 4 weeks but ≤ 6 weeks following the completion of temozolomide in the concomitant phase For patients enrolled into Stage II, they must be within ≥ 2 weeks but ≤ 6 weeks after primary GBM resection/biopsy The patient must have recovered from the definitive surgical procedure for GBM Patient is able to be assessed by periodic dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) scan Patient has Karnofsky performance status >= 60 Patient has adequate bone marrow and organ function Exclusion Criteria: Patient has received previous treatment with PI3K and/or mTOR inhibitors for GBM or for pre-existing neoplasm transformed to GBM. Patient has received any prior anti-neoplastic therapy for BKM, except for the treatment allowed in inclusion criteria Patient has any tumor progression after definitive GBM resection/ biopsy, except for the transformation from previous low grade glioma. Patient with a concurrent malignancy or malignancy within 3 years of study enrollment (with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer) Patient who had not recovered to grade 1 or better from any adverse events (except alopecia, nausea, vomiting) related to previous antineoplastic therapy before screening procedures are initiated, as allowed in inclusion criteria Patient has any of the following baseline mood disorders (not attributable to GBM) as judged by the Investigator or a Psychiatrist, or meets the cut-off score of ≥ 12 in the PHQ- 9 or a cut-off of ≥ 15 in the GAD-7 mood scale for reasons not attributable to GBM; or selects a positive response of '1, 2, 3' to question number 9 regarding potential for suicidal thoughts or ideation in the PHQ-9 (independent of the total score of the PHQ-9) Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) Active severe personality disorders (defined according to DSM-IV). Note: for patients with psychotropic treatments ongoing at baseline, the dose and the schedule should not be modified within the previous 6 weeks prior to start of study drug. ≥ CTCAE grade 3 anxiety Patient who is concurrently using any other approved or investigational anti-neoplastic agent Patient who has undergone the following invasive procedures: Major surgical procedure, open biopsy or significant traumatic injury < 14 days prior to starting study drug or has not recovered from side effects of such therapy, anticipation of need for invasive surgical procedure during the course of the study, biopsy within 7 days prior to starting study drug Patient has poorly controlled diabetes mellitus (HbA1c > 8%) Patient is currently receiving increasing or chronic treatment with corticosteroids or another immunosuppressive agent Patient is currently receiving an enzyme inducing anti-epileptic drug. The patient must have discontinued EIAED therapy for at least two weeks prior to starting study drug. Non-enzyme inducing anti-epileptic medication is allowed, except those listed in the protocol Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BKM120 + Temozolomide (Concomitant Phase)<br>Cranial radiation: Days 1 - 5 every 7 days for 42 days60 Gy in 30 fractions; Temozolomide: 75 mg/m2 Daily, orally; BKM120: 0, or 40, or 60, or 80 mg/d Daily, orally or Days 1-5 every 7 days, orally | Drug: BKM120 + temozolomide<br>* The investigational drug, BKM120, will be supplied as 10-mg and 50-mg hard gelatin capsules. BKM120 will be administered on a once daily dosing schedule at a dose of 40 mg, or 60 mg, or 80 mg, or 100 mg (p.o.), in combination with the approved dosing of temozolomide and SoC delivery of cranial irradiation for GBM. The patient will be dosed with BKM120 on a flat scale of mg/day and the dose of BKM120 will not be adjusted to body weight or body surface area. Patients should not eat for 2 hours after the administration of BKM120. Temozolomide in 5 mg, 20 mg, 100 mg, 140 mg, 180 mg or 250 mg capsules will be administered in combination with the investigational drug BKM120.<br>|
| Experimental: BKM120 + temozolomide with/without radiotherapy<br>Adjuvant phase cycle 1: Temozolomide 150 mg/m2 - Days 1 - 5 every 28 days Daily; BKM120 60, or 80, or 100 mg/d; Adjuvant phase cycle 2+: Temozolomide 200* mg/m2 - Day 1   5 every 28 days Daily BKM120 0, or 40, or 60, or 80 or 100 mg/d | Drug: BKM120 +temozolomide with/without radiotherapy<br>* The investigational drug, BKM120, will be supplied as 10-mg and 50-mg hard gelatin capsules. BKM120 will be administered on a continuous once daily dosing schedule at a dose of 40 mg, or 60 mg, or 80 mg, or 100 mg (p.o.), in combination with the approved dosing of temozolomide and SoC delivery of cranial irradiation for GBM. The patient will be dosed with BKM120 on a flat scale of mg/day and the dose of BKM120 will not be adjusted to body weight or body surface area. Patients should not eat for 2 hours after the administration of BKM120. Temozolomide in 5 mg, 20 mg, 100 mg, 140 mg, 180 mg or 250 mg capsules will be administered in combination with the investigational drug BKM120.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity (DLT) | Per DLT criteria as defined in protocol | Concomitant phase (42 days), adjuvant phase cycle 1 (28-day cycle), adjuvant phase cycles 2 (28-day cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| No of participants with Adverse events based on abnormal laboratory results, abnormal electrocardiogram (ECG) findings | Per common terminology criteria for adverse events (CTCAE) criteria (version 4.0) | Baseline, 30 days post the last BKM120 treatment | 
| Objective response rate (ORR) | Antitumor activity will be assessed using the Neuro-Oncology Working Group updated response assessment criteria for high grade gliomas - per RANO criteria. | Baseline, 18 months after first BKM120 treatment | 
| Progression free survival (PFS) | Per patient survival follow up feedbacks | at 12 months and at 18 months | 
| Overall survival (OS) | Per patient survival follow up feedbacks | Until death or consent withdrawal | 
| Plasma concentration-time profiles and basic pharmacokinetic parameters of BKM120 and temozolomide (Cmax, tmas, AUC, half-life) | Standard bioanalytical-pharmacokinetic (PK) analysis on PK samples for BKM120 and temozolomide. | baseline, Day 1, 8, 15, 28 in concomitant phase, Cycle 1 Day 1, 5 and Cycle 2 Day1, 5 at adjuvant phase (28-day per cycle) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BKM120, temozolomide, glioblastoma multiforme, GBM, Newly diagnosed