Clinical trial NCT01473901: A Phase I Dose Escalation Study of BKM120 With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Glioblastoma
Keywords: BKM120
temozolomide
glioblastoma multiforme
GBM
Newly diagnosed
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-11-17
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Dose Limiting Toxicity (DLT)
timeFrame: Concomitant phase (42 days), adjuvant phase cycle 1 (28-day cycle), adjuvant phase cycles 2 (28-day cycle)
Secondary outcomes:
measure: No of participants with Adverse events based on abnormal laboratory results, abnormal electrocardiogram (ECG) findings
timeFrame: Baseline, 30 days post the last BKM120 treatment
measure: Objective response rate (ORR)
timeFrame: Baseline, 18 months after first BKM120 treatment
measure: Progression free survival (PFS)
timeFrame: at 12 months and at 18 months
measure: Overall survival (OS)
timeFrame: Until death or consent withdrawal
measure: Plasma concentration-time profiles and basic pharmacokinetic parameters of BKM120 and temozolomide (Cmax, tmas, AUC, half-life)
timeFrame: 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)
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Highlands Oncology Group Highlands Oncology
state: Arkansas
city: Boston
country: United States
facility: Dana Farber Cancer Institute SC (1)
state: Massachusetts
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center MD Anderson DeGrout
state: Texas
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Hamilton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Wen PY, Rodon JA, Mason W, Beck JT, DeGroot J, Donnet V, Mills D, El-Hashimy M, Rosenthal M. Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. ESMO Open. 2020 Jul;5(4):e000673. doi: 10.1136/esmoopen-2020-000673.