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

Phase I/II Study of the Combination of BKM120 and Bevacizumab in Patients With Refractory Solid Tumors (Phase I) and Relapsed/Refractory Glioblastoma Multiforme (Phase II)

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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma Multiforme
• Intervention / Treatment: Drug: Bevacizumab; Drug: BKM120

Detailed Description

This is an open-label, non-randomized Phase I study of patients with advanced refractory solid tumors followed by a Phase II study for the second-line treatment of patients with relapsed/refractory glioblastoma multiforme.

In the phase I part of the study the optimal dose of BKM120 when combined with bevacizumab was determined. In the Phase II part of this study, patients with relapsed/refractory GBM following first line therapy are being treated with the BKM120/bevacizumab combination. Limited BKM120 pharmacokinetic evaluation will be performed on all patients treated during this part of the study. Patients will be reevaluated for response to treatment after 2 cycles (8 weeks). Patients with objective response or stable disease will continue treatment, with subsequent reevaluations every 8 weeks, until disease progression or unacceptable toxicity occurs.

Two populations of patients with relapsed/refractory GBM will be treated in the Phase II trial: 1) patients with no previous exposure to bevacizumab (N= 55) and 2) patients who received bevacizumab as part of first-line combined modality treatment (N= 20).

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale School of Medicine
  • Florida
    • Fort Myers, Florida, United States, 33916
      • Florida Cancer Specialists
    • Orlando, Florida, United States, 32804
      • Florida Hospital Cancer Institute
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Center for Cancer and Blood Disorders
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Grand Rapids Oncology Program
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Nebraska Methodist Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

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.

Exclusion Criteria:

• 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.
• Patients with any history of a bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
• Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must recover to a grade 1 before starting the trial.
• Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) ≤ 5 effective half lives prior to starting study drug or who have not recovered from side effects of such therapy.
• Patients who have been treated with any hematopoietic colony-stimulating factors (e.g. G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment may be continued.
• Major surgical procedure, open biopsy, intracranial biopsy, ventriculoperitoneal shunt or significant traumatic injury ≤ 28 days prior to entry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BKM120/Bevacizumab; 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; Bevacizumab 10 mg/kg IV every 2 weeks; Other Names: Avastin; Drug: BKM120; BKM120 orally (PO) once daily; Other Names: Buparlisib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response (CR or PR) of Phase II Participants - Prior Bevacizumab and Bevacizumab Naive	Two groups of participants in the Phase II trial will be considered separately, 1) those who have not received previous bevacizumab and 2) those who have received bevacizumab as part of first-line treatment. Overall Response (OR) = number of patients with complete or partial responses (CR or PR) per McDonald or RANO criteria. McDonald: CR as disappearance of all disease for at least four weeks, no new lesions, no steroids; PR as 50% or greater decrease in the sum of all lesions compared with baseline for at least four weeks, no new lesions, stable or reduced steroids (McDonald 1990). RANO: CR as disappearance of all disease for at least 4 weeks, no new lesions, stable or improved nonenhancing lesions, and no steroid usage; and PR as a 50% or greater decrease in the sum of all lesions compared with baseline measurement for at least four weeks, no new lesions, stable or improved nonenhancing lesions on same or lower steroid dose compared to baseline (Wen 2010).	every 8 weeks, projected 24 months
Median Overall Survival (OS) 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. Overall survival is measured as the interval from first study treatment until date of death, or date last known alive.	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	Defined as the number of participants with treatment-emergent grade 3/4/5 adverse events/serious adverse events utilizing the National Cancer Institute Common Technology Criteria for Adverse Events (NCI CTCAE) v4.03	every 4 weeks for up to 5.2 years

Collaborators and Investigators

• Sponsor: SCRI Development Innovations, LLC
• Collaborators: Novartis
• Investigators: Study Chair: Kent Shih, MD, Sarah Cannon

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• Bleehen NM, Stenning SP. A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party. Br J Cancer. 1991 Oct;64(4):769-74. doi: 10.1038/bjc.1991.396.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 29, 2018

Study Registration Dates

• First Submitted: April 25, 2011
• First Submitted That Met QC Criteria: May 5, 2011
• First Posted (Estimate): May 6, 2011

Study Record Updates

• Last Update Posted (Actual): June 17, 2020
• Last Update Submitted That Met QC Criteria: June 8, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: GBM; Bevacizumab; Glioblastoma multiforme; BKM120; PI3K Pathway
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: SCRI CNS 13