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

Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01473901
• Other study ID #: CBKM120E2101
• Secondary ID: 2011-001157-87
• Status: Completed
• Phase: Phase 1
• Start date: December 30, 2011
• Est. completion date: May 17, 2017

Study information

• Verified date: September 2017
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: May 17, 2017
• Est. primary completion date: May 17, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Glioblastoma

Intervention

Drug:
• BKM120 + temozolomide
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.
• BKM120 +temozolomide with/without radiotherapy
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.

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Melbourne	Victoria
Canada	Novartis Investigative Site	Hamilton	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
United States	Dana Farber Cancer Institute SC (1)	Boston	Massachusetts
United States	Highlands Oncology Group Highlands Oncology	Fayetteville	Arkansas
United States	University of Texas/MD Anderson Cancer Center MD Anderson DeGrout	Houston	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Progression free survival (PFS)	Per patient survival follow up feedbacks	at 12 months and at 18 months
Secondary	Overall survival (OS)	Per patient survival follow up feedbacks	Until death or consent withdrawal
Secondary	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)

External Links

•   Results for CBKM120E2101 can be found on the Novartis Clinical Trial Results Website