LBH589 and Bevacizumab in Patients With Recurrent High Grade Glioma

NCT00859222 | Completed Phase 1 Results DMC

• 2 other identifiers: 08-342CLBH589BUS42T
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 5

Brief Summary

The purpose of this research study is to determine the amount of LBH589 that can be given to people safely when LBH589 is given in combination with bevacizumab. LBH589 in combination with bevacizumab is a drug combination that may stop cancer cells from growing abnormally. LBH589 has been used alone in other trials for solid tumor malignancies. Bevacizumab is FDA approved for use in patients with colorectal cancer and has been studied extensively in other types of solid tumors. The combination of LBH589 and bevacizumab has not yet been studied but information from other studies suggests that the combination may help prevent the growth of the participant's tumor.

Conditions

Malignant Glioma

Keywords

LBH589; bevacizumab; Avastin; Panobinostat

Outcome Measures

Primary Outcomes (3)

• LBH589 Maximum Tolerated Dose (MTD) [Phase I]

  The MTD LBH589 in combination with bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached but the highest dose received may be the Recommended Phase II Dose (RP2D). The MTD was not reached with 0 of 6 DLTs observed in the highest dose cohort but due to safety concerns higher doses of LBH589 with bevacizumab were neither planned nor tested. The RP2D was 30 mg/day orally, 3x per week, every other week.

  Participants were assessed every 2 weeks while on study; The observation period for MTD evaluation was the first 30 days of treatment.

• Dose Limiting Toxicity (DLT) [Phase I]

  A DLT was defined as an adverse event that (a) is related to the LBH589 and/or bevacizumab with an attribution of possible, probable, or definite, and (b) occurs during and/or begins during the first 30 days of the study treatment, and (c) meets any of the following criteria: grade 3 thrombocytopenia; grade 4 neutropenia lasting 7 days; grade 4 anemia lasting 7 days despite transfusion or growth factors; febrile neutropenia if ANC\<0.5 x10\^9/L; a QT interval corrected for heart rate (QTc) of 500-515 msec that did not stabilize to \<480 msec after one week; a second occurrence of QTc 500-515 msec; any QTc \>515 msec; any deep vein thrombosis (DVT) or pulmonary embolism (PE) while on fully therapeutic anticoagulation therapy; Grade 3 proteinuria lasting 14 days; or any other clinically significant Grade 3 toxicity despite maximal medical therapy lasting 7 days, any Grade 4 toxicity despite maximal medical therapy; or any Grade 3 or 4 toxicity resulting in study drug discontinuation.

  Participants were assessed every 2 weeks while on study; The observation period for DLT evaluation was the first 30 days of treatment.

• 6-Month Progression-Free Survival (PFS6) [Phase II]

  PFS6 is the proportion of patients remaining alive and progression-free at 6-months from study entry. Progressive disease was established based on RANO criteria (Wen et al JCO 2010).

  Disease was assessed radiographically to document clinical progression every cycle on treatment and post-treatment every 8 weeks up to 12 months. Participants were followed for PFS6 up to 6 months since study entry.

Secondary Outcomes (3)

• Best Radiographic Response

  Disease was assessed radiographically for response every cycle on treatment. Treatment duration in cycles was a median (range) of 2 (1-6) PI Cohort 1, 4.5 (2-6) PI Cohort 2, 6 (2-10) PI Cohort 3, 5 PII GBM and 7 PII AG.

• Progression-Free Survival (PFS) [Phase II]

  Disease was assessed radiographically to document clinical progression every cycle on treatment and post-treatment every 8 weeks up to 12 months.

• Overall Survival [Phase II]

  Participants were followed long-term for survival every 4 months from the end of treatment until death or lost to follow-up. Phase II participants were followed for OS up to 27 months on this study.

Other Outcomes (3)

• Progression-Free Survival (PFS) [Phase I]

  Disease was assessed radiographically to document clinical progression every cycle on treatment and post-treatment every 8 weeks up to 12 months.

• 6-Month Progression-Free Survival (PFS6) [Phase I]

  Disease was assessed radiographically to document clinical progression every cycle on treatment and post-treatment every 8 weeks up to 12 months. Participants were followed for PFS6 up to 6 months since study entry.

• Overall Survival (OS) [Phase I]

  Participants were followed long-term for survival every 4 months from the end of treatment until death or lost to follow-up. Phase I participants were followed for OS up to 12.1 months on this study.

Study Arms (7)

Phase I Cohort 1: Bevacizumab +LBH589 20 mg every week

EXPERIMENTAL

Phase I Cohort 1 participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and the original starting LBH589 dose of 20 mg/day orally, 3x per week, every week (days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26). Participants were treated until disease progression or unacceptable toxicity.

Drug: LBH589; Drug: bevacizumab

Phase I Cohort 2: Bevacizumab + LBH589 20 mg every other week

EXPERIMENTAL

Phase I Cohort 2 participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and the amended starting LBH589 dose of 20 mg/day orally, 3x per week, every other week (Days 1, 3, 5, 15, 17, 19). Participants were treated until disease progression or unacceptable toxicity.

Drug: LBH589; Drug: bevacizumab

Phase I Cohort 3: Bevacizumab + LBH589 30 mg every other week

EXPERIMENTAL

Phase I Cohort 3 participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and LBH589 30 mg/day orally, 3x per week, every other week (Days 1, 3, 5, 15, 17, 19). Participants were treated until disease progression or unacceptable toxicity.

Drug: LBH589; Drug: bevacizumab

All Phase I Participants

EXPERIMENTAL

All phase I participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and LBH589 according to the established dose escalation schedule. Participants were treated until disease progression or unacceptable toxicity.

Drug: LBH589; Drug: bevacizumab

Phase II GBM: Bevacizumab + LBH589 30 mg every other week

EXPERIMENTAL

Phase II glioblastoma (GBM) participants received the regimen established in the Phase I study (Feb 2011). Phase II participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and LBH589 30 mg/day orally, 3x per week, every other week (Days 1, 3, 5, 15, 17, 19). Participants were treated until disease progression or unacceptable toxicity.

Drug: LBH589; Drug: bevacizumab

Phase II AG: Bevacizumab + LBH589 30 mg every other week

EXPERIMENTAL

Phase II Anaplastic Glioma (AG) participants received the regimen established in the Phase I study (Feb 2011). Phase II participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and LBH589 30 mg/day orally, 3x per week, every other week (Days 1, 3, 5, 15, 17, 19). Participants were treated until disease progression or unacceptable toxicity.

Drug: LBH589; Drug: bevacizumab

All Phase II Participants

EXPERIMENTAL

All phase II participants received bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle and LBH589 30 mg/day orally, 3x per week, every other week (Days 1, 3, 5, 15, 17, 19). Participants were treated until disease progression or unacceptable toxicity.

Drug: LBH589; Drug: bevacizumab

Interventions

LBH589 DRUG

Also known as: panobinostat, Farydak

All Phase I Participants; All Phase II Participants; Phase I Cohort 1: Bevacizumab +LBH589 20 mg every week; Phase I Cohort 2: Bevacizumab + LBH589 20 mg every other week; Phase I Cohort 3: Bevacizumab + LBH589 30 mg every other week; Phase II AG: Bevacizumab + LBH589 30 mg every other week; Phase II GBM: Bevacizumab + LBH589 30 mg every other week

bevacizumab DRUG

Also known as: Avastin

All Phase I Participants; All Phase II Participants; Phase I Cohort 1: Bevacizumab +LBH589 20 mg every week; Phase I Cohort 2: Bevacizumab + LBH589 20 mg every other week; Phase I Cohort 3: Bevacizumab + LBH589 30 mg every other week; Phase II AG: Bevacizumab + LBH589 30 mg every other week; Phase II GBM: Bevacizumab + LBH589 30 mg every other week

Eligibility Criteria

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

You may qualify if:

• Provide written informed consent prior to participation in the study and any related procedures being performed.
• Agreed to and signed an authorization for the release of their protected health information.
• Must be 18 years of age or older
• Karnofsky Performance Status 60 or greater
• Life expectancy of at least 8 weeks
• Histologic diagnosis of GBM, gliosarcoma, anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), or anaplastic mixed oligoastrocytoma (AMO) (Patients are eligible if the original histology was lower-grade glioma)
• Unequivocal progression by magnetic resonance imaging (MRI) or computed tomography (CT) scan. A scan must be performed within 14 days prior to registration and on a steroid dose that has been stable for at least 5 days. (Patients with recurrence who undergo resection and are left without measurable or evaluable disease are eligible.)
• Patients must have failed prior radiation therapy and must have an interval of greater than or equal to 60 days from the completion of radiation therapy to study entry.
• Patients must have recovered from the toxic effects of prior therapy. Residual toxicity from any previous treatment must be Grade 1 or less.
• Sufficient time for recovery from prior therapy: 28 days from any investigational agent, 28 days from prior cytotoxic therapy(except 23 days from prior temozolomide, 14 days from vincristine, 42 days from nitrosoureas, 21 days from procarbazine administration), and 7 days for non-cytotoxic agents.
• Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis based upon positron emission tomography (PET), Thallium scanning, MR spectroscopy or surgical documentation of disease.
• Subjects who have undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: a) prior to initiating therapy, 4 weeks must have elapsed since surgery (Subjects must have recovered from surgical-related trauma. Wound healing needs to have occurred.) b) residual disease following resection of recurrent malignant glioma is not mandated for eligibility. To assess the extent of residual disease postoperatively, a MRI or CT should be done at least 4 weeks postoperatively and within 14 days prior to registration.
• Clinical laboratory tests within 14 days prior to enrollment meeting the criteria listed in the protocol
• Cardiology assessment: Baseline MUGA or Echocardiogram must demonstrate LVEF 50% or greater
• Electrocardiogram: A single screening ECG, taken within 14 days of registration, will be performed to assess study eligibility. Patients whose single QTc interval is ≤ 450 msec are eligible. Patients whose QTc interval is \> 460 msec are ineligible. If the result is \> 450 msec and ≤ 460 msec, two additional ECG readings are to be performed, each one separated by at least 5 minutes; in this case to be eligible, each individual QTc interval must be ≤ 460 msec and the average of the QTc intervals must be ≤ 450 msec.

You may not qualify if:

• Subject has received previous therapy with anti-VEGF targeted agents or with any histone deacetylase inhibitors. (Prior treatment with valproic acid for seizures is allowed but requires a washout of at least 14 days prior to starting LBH589.) Although concomitant use of the following drugs is not allowed on study, previous use is allowed, provided patients meet the following mandatory washout periods:
• i. Drugs w/ risk of causing TdP = 72 hrs; ii. Warfarin = 7 days.
• History of grade 2 thrombocytopenia or grade 3 neutropenia on any prior regimen.
• Presence of ≥ grade 2 peripheral neuropathy.
• Bleeding diathesis or coagulopathy
• History of intratumoral or peritumoral hemorrhage if deemed significant by the treating physician
• Treatment with warfarin. (For patients requiring anticoagulation therapy, only therapeutic low molecular weight heparin or factor Xa inhibitors are permitted.)
• Patients who have received any investigational drug or undergone major surgery \< 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
• Any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy
• Patients with any disease that will obscure toxicity or dangerously alter drug metabolism
• Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and has not received treatment for that particular disease for a minimum of 3 years
• Impaired cardiac function as detailed in the protocol
• Uncontrolled hypertension (systolic blood pressure \>/= 140 mmHg and/or diastolic blood pressure \>/= 90 mmHg) and/or prior history of hypertensive crisis or hypertensive encephalopathy
• Significant vascular disease within 6 months prior to Day 1
• History of stroke or transient ischemic attack within 6 months prior to Day 1

Sponsors & Collaborators

• Patrick Y. Wen, MD: lead
• Brigham and Women's Hospital: collaborator
• Massachusetts General Hospital: collaborator
• Beth Israel Deaconess Medical Center: collaborator
• Northwestern University: collaborator
• University of Virginia: collaborator
• Genentech, Inc.: collaborator
• Novartis: collaborator

Study Sites (5)

Northwestern University

Chicago, Illinois, 60611, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Beth-Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

University of Virginia, Department of Neurology

Charlottesville, Virginia, 22908, United States

Location

Related Publications (2)

• Drappatz J, Lee EQ, Hammond S, Grimm SA, Norden AD, Beroukhim R, Gerard M, Schiff D, Chi AS, Batchelor TT, Doherty LM, Ciampa AS, Lafrankie DC, Ruland S, Snodgrass SM, Raizer JJ, Wen PY. Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma. J Neurooncol. 2012 Mar;107(1):133-8. doi: 10.1007/s11060-011-0717-z. Epub 2011 Oct 8.

  PMID: 21984064 RESULT

• Lee EQ, Reardon DA, Schiff D, Drappatz J, Muzikansky A, Grimm SA, Norden AD, Nayak L, Beroukhim R, Rinne ML, Chi AS, Batchelor TT, Hempfling K, McCluskey C, Smith KH, Gaffey SC, Wrigley B, Ligon KL, Raizer JJ, Wen PY. Phase II study of panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma. Neuro Oncol. 2015 Jun;17(6):862-7. doi: 10.1093/neuonc/nou350. Epub 2015 Jan 7.

  PMID: 25572329 RESULT

MeSH Terms

Conditions

Glioma

Interventions

Panobinostat; Bevacizumab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Patrick Y. Wen, MD
• Organization: Dana-Farber Cancer Institute

Patrick_Wen@dfci.harvard.edu

617-632-2166

Study Officials

• Patrick Y. Wen, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director, Center For Neuro-Oncology

Study Record Dates

• First Submitted: March 9, 2009
• First Posted: March 10, 2009
• Study Start: March 1, 2009
• Primary Completion: September 1, 2013
• Study Completion: December 1, 2015
• Last Updated: March 14, 2017
• Results First Posted: November 28, 2016

Record last verified: 2017-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)