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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by SCRI Development Innovations, LLC
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
SCRI Development Innovations, LLC
ClinicalTrials.gov Identifier:
NCT01349660
First received: April 25, 2011
Last updated: May 9, 2014
Last verified: March 2014
  Purpose

In this phase I/II study, the investigators plan to evaluate 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.


Condition Intervention Phase
Glioblastoma Multiforme
Drug: Bevacizumab
Drug: BKM120
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by SCRI Development Innovations, LLC:

Primary Outcome Measures:
  • To establish the optimal dose of BKM120 that can be administered in combination with a standard dose of bevacizumab. (Phase I) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • To evaluate the efficacy of the BKM120/bevacizumab combination in patients with relapsed/refractory GBM. [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    For evaluation of efficacy, patients previously treated with bevacizumab will be considered separately from those with no previous bevacizumab treatment.


Secondary Outcome Measures:
  • To evaluate the toxicity of the BKM120/bevacizumab combination. [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
    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.

  • To evaluate the pharmacokinetics of BKM120 when administered concurrently with bevacizumab [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]

    The purposes of PK sampling are:

    1. to detect any alteration in BKM120 PK caused by concurrent administration of bevacizumab
    2. to detect any alterations in patients receiving concurrent treatment with mild CYP3A4 inhibitors or inducers.


Estimated Enrollment: 93
Study Start Date: December 2011
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BKM120/Bevacizumab
Combination of BKM120 and Bevacizumab
Drug: Bevacizumab
Bevacizumab 10 mg/kg IV every 2 weeks
Other Name: Avastin
Drug: BKM120
BKM120 PO once daily

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.

The phase I study will determine the MTD of BKM120 when combined with bevacizumab. The Phase I portion will follow a standard dose escalation design, beginning with dose level 1. The sequence of dose escalation for BKM120 and bevacizumab is based on a starting dose of 60 mg/day for BKM120 (i.e. 50% of the MTD of BKM120 when administered as a single agent). A maximum of three BKM120 dose levels will be evaluated. Bevacizumab will be fixed at 10 mg/kg IV and will be administered every two weeks. Approximately 18 patients will be enrolled during the Phase I portion to establish the MTD.

In the Phase II portion of this study, patients with relapsed/refractory GBM following first line therapy will receive treatment with the BKM120/bevacizumab combination. Limited BKM120 pharmacokinetic evaluation will be performed on all patients treated during the Phase II portion 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).

  Eligibility

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

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 per adapted MacDonald criteria
  • Archival tumor tissue available for correlative testing for identification of PI3K pathway activation.

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 function defined by:

    • Absolute neutrophil count (ANC) ≥1500/μL
    • Hemoglobin (Hgb) ≥ 9 g/dL
    • Platelets ≥ 100,000/µL
  • Adequate liver function defined by:

    • Alanine aminotransferase (AST) or aspartate aminotransferase (ALT) within normal limits (WNL) (or ≤ 3.0 x upper limit of normal (ULN) in patients with liver metastases
    • Serum bilirubin WNL (or ≤ 1.5 x the institutional ULN in patients with liver metastases; or total bilirubin ≤ 3.0 x ULN with direct bilirubin WNL in patients with well documented Gilbert Syndrome).
  • Adequate renal function, defined by:

    •Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 mL/min

  • Urine dipstick for proteinuria < 2+ at screening. Patients with dipstick urinalysis ≥2+ proteinuria at baseline should undergo a 24 hour urine collection, and must demonstrate ≤ 1 g of protein/24 hours to be eligible.

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.
  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: NCT01349660

Contacts
Contact: John Hainsworth, M.D. 877-691-7274 asksarah@scresearch.net
Contact: Trials Info 877-691-7274 asksarah@scresearch.net

Locations
United States, Connecticut
Yale School of Medicine Recruiting
New Haven, Connecticut, United States, 06520
United States, Florida
Florida Cancer Specialists Recruiting
Ft. Myers, Florida, United States, 33916
Florida Hospital Cancer Institute Recruiting
Orlando, Florida, United States, 32804
Woodlands Medical Specialists Recruiting
Pensacola, Florida, United States, 32503
Florida Cancer Specialists Recruiting
St. Petersburg, Florida, United States, 33705
United States, Maryland
Center for Cancer and Blood Disorders Recruiting
Bethesda, Maryland, United States, 20817
United States, Michigan
Grand Rapids Oncology Program Recruiting
Grand Rapids, Michigan, United States, 49503
Principal Investigator: Gilbert Padula, MD         
United States, Missouri
St. Louis Cancer Care Recruiting
Chesterfield, Missouri, United States, 63017
United States, Nebraska
Nebraska Methodist Hospital Recruiting
Omaha, Nebraska, United States, 68114
United States, Tennessee
Tennessee Oncology Recruiting
Nashville, Tennessee, United States, 37203
United States, Virginia
Peninsula Cancer Institute Recruiting
Newport News, Virginia, United States, 23601
Virginia Cancer Institute Recruiting
Richmond, Virginia, United States, 23235
Sponsors and Collaborators
SCRI Development Innovations, LLC
Novartis
Investigators
Study Chair: John Hainsworth, MD SCRI Development Innovations, LLC
  More Information

No publications provided

Responsible Party: SCRI Development Innovations, LLC
ClinicalTrials.gov Identifier: NCT01349660     History of Changes
Other Study ID Numbers: SCRI CNS 13
Study First Received: April 25, 2011
Last Updated: May 9, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by SCRI Development Innovations, LLC:
Glioblastoma multiforme
GBM
Bevacizumab
PI3K Pathway
BKM120

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
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 28, 2014