Combination of BKM120 and Bevacizumab in Refractory Solid Tumors and Relapsed/Refractory Glioblastoma Multiforme

NCT01349660 | Completed Phase 1 Results

• 1 other identifier: SCRI CNS 13
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 8

Brief Summary

In this phase I/II study,investigators are evaluating the feasibility and efficacy of the combination of BKM120, an oral inhibitor of PI3 kinase, and bevacizumab in the treatment of patients with relapsed/refractory GBM. In the Phase I part of the trial, the optimal BKM120 dose to be administered with a standard dose of bevacizumab will be determined in patients with refractory solid tumors. Although it is unlikely that the concurrent administration of bevacizumab will alter the pharmacokinetics of BKM120, limited pharmacokinetic sampling will be performed on all patients treated during the Phase II portion of the study. Assuming this combination is feasible, the Phase II portion of the study will proceed, using the doses determined in the Phase I portion. In the phase II portion, eligible patients will be limited to those with recurrent/progressive GBM following 1st line combined modality therapy.

Conditions

Glioblastoma Multiforme

Keywords

Glioblastoma multiforme; GBM; Bevacizumab; PI3K Pathway; BKM120

Outcome Measures

Primary Outcomes (2)

• Number of Phase I Patients Receiving 60mg or 80mg BKM120 Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Optimal Dosage

  The optimal dose of BKM120 to administer in combination with standard dose bevacizumab determined as the dose at which ≤1 of 6 patients experiences a DLT assessed using NCI CTCAE v4.03 during Cycle 1 (28 days). The optimal dose of BKM120 was determined to be 60 mg by mouth (PO), once a day for each 28 day cycle along with bevacizumab, administered 10 mg/kg intravenously (IV) on Day 1 and Day 15 of each 28 day cycle.

  Collected from day of first dose to the end of the first treatment cycle, up to 28 days

• Median Progression-Free Survival (PFS) in Phase II Participants - Prior Bevacizumab and Bevacizumab Naive

  Two groups of patients in the Phase II trial will be considered separately, 1) participants who have not received previous bevacizumab and 2) participants who have received bevacizumab as part of first-line treatment. PFS is measured from the date of first protocol treatment until date of disease progression or death occurs, or date of last adequate tumor assessment using RANO or McDonald criteria. McDonald disease progression criteria: a 25% or greater increase in sum of the diameters of lesions, new lesions, or clinical deterioration (McDonald et al, 1990). RANO disease progression criteria: a 25% or greater increase in the enhancing lesions sum compared with smallest tumor measurement, significant increase in T2/FLAIR nonenhancing lesion on stable or increasing corticosteroids, new lesions, or clinical deterioration (Wen et al 2010)

  every 8 weeks for up to 33 months

Secondary Outcomes (3)

• Overall Response (CR or PR) of Phase II Participants - Prior Bevacizumab and Bevacizumab Naive

  every 8 weeks, projected 24 months

• Median Overall Survival (OS) in Phase II Participants - Prior Bevacizumab and Bevacizumab Naive

  every 12 weeks for up to 60 months

• Number of Participants With Grade 3/4/5 Serious Adverse Events and Adverse Events as a Measure of Safety and Tolerability

  every 4 weeks for up to 5.2 years

Study Arms (1)

BKM120/Bevacizumab

EXPERIMENTAL

Phase I: BKM 120 orally (PO) once daily (dose is 60mg or 80mg). Bevacizumab: 10mg/kg intravenous (IV) every 2 weeks Phase II: BKM 120 orally (PO) once daily - dose is optimal dose determined in Phase I. Bevacizumab: 10mg/kg intravenous (IV) every 2 weeks

Drug: Bevacizumab; Drug: BKM120

Interventions

Bevacizumab DRUG

Bevacizumab 10 mg/kg IV every 2 weeks

Also known as: Avastin

BKM120/Bevacizumab

BKM120 DRUG

BKM120 orally (PO) once daily

Also known as: Buparlisib

BKM120/Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Phase I ONLY:
• Advanced, metastatic solid tumor that has progressed after standard therapy, or is a tumor type resistant to therapy, and for which bevacizumab is clinically appropriate.
• Patient may have measurable disease or non-measureable disease as defined by RECIST v1.1 criteria
• Phase II ONLY:
• Progressive GBM after treatment with surgical resection (if possible) and 1st line radiation/chemotherapy.
• No previous treatment with a PI3K inhibitor. Previous treatment with bevacizumab as a component of first-line therapy is allowed.
• At least one measurable or evaluable lesion definable by MRI scan. Disease must be measurable by RANO criteria.
• Archival tumor tissue available for correlative testing.
• ALL PATIENTS:
• Patient must be ≥ 4 weeks from administration of last dose of cancer therapy (including radiation therapy, biologic therapy, hormonal therapy, or chemotherapy). Patients who receive a small molecule targeted therapy as part of their first line treatment regimen must be ≥ 4 weeks or ≥ 5 half lives from administration of last dose, whichever is shorter. The patient must have recovered from or come to a new chronic or stable baseline from all treatment-related toxicities.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Life expectancy of ≥ 3 months.
• Adequate hematologic, hepatic, and renal function.

You may not qualify if:

• Patients with diarrhea ≥ grade 2.
• Patients with uncontrolled type I or type II diabetes mellitus, defined as a fasting plasma glucose ≥120 mg/dL.
• Patients who have received prior treatment with a P13K inhibitor.
• Treatment with therapeutic doses of coumarin-type anticoagulants (maximum daily dose of 1 mg allowed for port line patency permitted).
• Patient has active cardiac disease including any of the following:
• Left ventricular ejection fraction (LVEF) \< 50% as determined by Multiple Grated acquisition (MUGA) scan or echocardiogram (ECHO)
• QTc \> 480 msec on screening ECG (using the QTcF formula)
• Angina pectoris that requires the use of anti-anginal medication
• Ventricular arrhythmias except for benign premature ventricular contractions
• Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
• Conduction abnormality requiring a pacemaker
• Valvular disease with documented compromise in cardiac function
• Symptomatic pericarditis
• Patients who are currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug.
• Patients with clinical history of hemoptysis or hematemesis (defined as having bright red blood of ½ teaspoon or more per episode) ≤1 month prior to study enrollment.

Sponsors & Collaborators

• SCRI Development Innovations, LLC: lead
• Novartis: collaborator

Study Sites (8)

Yale School of Medicine

New Haven, Connecticut, 06520, United States

Location

Florida Cancer Specialists

Fort Myers, Florida, 33916, United States

Location

Florida Hospital Cancer Institute

Orlando, Florida, 32804, United States

Location

Florida Cancer Specialists

St. Petersburg, Florida, 33705, United States

Location

Center for Cancer and Blood Disorders

Bethesda, Maryland, 20817, United States

Location

Grand Rapids Oncology Program

Grand Rapids, Michigan, 49503, United States

Location

Nebraska Methodist Hospital

Omaha, Nebraska, 68114, United States

Location

Tennessee Oncology

Nashville, Tennessee, 37203, United States

Location

Related Publications (8)

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  PMID: 1654987 BACKGROUND

• Bokstein F, Shpigel S, Blumenthal DT. Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer. 2008 May 15;112(10):2267-73. doi: 10.1002/cncr.23401.

  PMID: 18327820 BACKGROUND

• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

  PMID: 19097774 BACKGROUND

• Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.

  PMID: 15758009 BACKGROUND

• Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007 Oct 20;25(30):4722-9. doi: 10.1200/JCO.2007.12.2440.

  PMID: 17947719 BACKGROUND

• Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010 Apr 10;28(11):1963-72. doi: 10.1200/JCO.2009.26.3541. Epub 2010 Mar 15.

  PMID: 20231676 BACKGROUND

• Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990 Jul;8(7):1277-80. doi: 10.1200/JCO.1990.8.7.1277.

  PMID: 2358840 BACKGROUND

• Chakravarti A, Zhai G, Suzuki Y, Sarkesh S, Black PM, Muzikansky A, Loeffler JS. The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J Clin Oncol. 2004 May 15;22(10):1926-33. doi: 10.1200/JCO.2004.07.193.

  PMID: 15143086 BACKGROUND

MeSH Terms

Conditions

Glioblastoma

Interventions

Bevacizumab; NVP-BKM120

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Charles Davis, RAC
• Organization: Sarah Cannon Development Innovations

Charles.Davis2@scri-innovations.com

Study Officials

• Kent Shih, MD

  Sarah Cannon

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 25, 2011
• First Posted: May 6, 2011
• Study Start: December 1, 2011
• Primary Completion: December 1, 2016
• Study Completion: December 29, 2018
• Last Updated: June 17, 2020
• Results First Posted: January 31, 2018

Record last verified: 2020-06

Locations

US (8)