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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01473901
First received: August 18, 2011
Last updated: August 21, 2014
Last verified: August 2014
  Purpose

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


Condition Intervention Phase
Glioblastoma
Drug: BKM120 + temozolomide
Drug: BKM120 +temozolomide with/without radiotherapy
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Dose Limiting Toxicity (DLT) [ Time Frame: Concomitant phase (42 days), adjuvant phase cycle 1 (28-day cycle), adjuvant phase cycles 2 (28-day cycle) ] [ Designated as safety issue: Yes ]
    Per DLT criteria as defined in protocol


Secondary Outcome Measures:
  • No of participants with Adverse events based on abnormal laboratory results, abnormal electrocardiogram (ECG) findings [ Time Frame: Baseline, 30 days post the last BKM120 treatment ] [ Designated as safety issue: Yes ]
    Per common terminology criteria for adverse events (CTCAE) criteria (version 4.0)

  • Objective response rate (ORR) [ Time Frame: Baseline, 18 months after first BKM120 treatment ] [ Designated as safety issue: No ]
    Antitumor activity will be assessed using the Neuro-Oncology Working Group updated response assessment criteria for high grade gliomas - per RANO criteria.

  • Progression free survival (PFS) [ Time Frame: at 12 months and at 18 months ] [ Designated as safety issue: Yes ]
    Per patient survival follow up feedbacks

  • Overall survival (OS) [ Time Frame: Until death or consent withdrawal ] [ Designated as safety issue: Yes ]
    Per patient survival follow up feedbacks

  • Plasma concentration-time profiles and basic pharmacokinetic parameters of BKM120 and temozolomide (Cmax, tmas, AUC, half-life) [ Time Frame: 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) ] [ Designated as safety issue: Yes ]
    Standard bioanalytical-pharmacokinetic (PK) analysis on PK samples for BKM120 and temozolomide.


Estimated Enrollment: 50
Study Start Date: December 2011
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BKM120 + Temozolomide (Concomitant Phase)
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
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.
Experimental: BKM120 + temozolomide with/without radiotherapy

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
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01473901

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

Locations
United States, Arkansas
Highlands Oncology Group Highlands Recruiting
Fayetteville, Arkansas, United States, 72703
Contact: Holly Kinser    +1 479 872 8130    hkinser@hogonc.com   
Principal Investigator: Joseph Thaddeus Beck         
United States, Massachusetts
Dana Farber Cancer Institute SC (1) Recruiting
Boston, Massachusetts, United States, 02115
Contact: Edwin S Nunez    617-632-6749    enunez2@partners.org   
Principal Investigator: Patrick Y. Wen         
United States, Texas
University of Texas/MD Anderson Cancer Center MD Anderson DeGrout Recruiting
Houston, Texas, United States, 77030-4009
Contact: Georgina Mosquera    713-792-7255    gmosquer@mdanderson.org   
Principal Investigator: John F DeGroot         
Australia, Victoria
Novartis Investigative Site Recruiting
Parkville, Victoria, Australia, 3050
Canada, Ontario
Novartis Investigative Site Recruiting
Hamilton, Ontario, Canada, L8V 5C2
Novartis Investigative Site Recruiting
Toronto, Ontario, Canada, M5G 2M9
Spain
Novartis Investigative Site Recruiting
Barcelona, Cataluña, Spain, 08035
Novartis Investigative Site Recruiting
Madrid, Spain, 28040
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01473901     History of Changes
Other Study ID Numbers: CBKM120E2101, 2011-001157-87
Study First Received: August 18, 2011
Last Updated: August 21, 2014
Health Authority: United States: Food and Drug Administration
Australia: Government Therapeutic Goods Administration (TGA)
Canada: Health Canada
Spain: Spanish Agency of Medicines

Keywords provided by Novartis:
BKM120
temozolomide
glioblastoma multiforme
GBM
Newly diagnosed

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 18, 2014