Ph II SAHA and Bevacizumab for Recurrent Malignant Glioma Patients

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01738646
• Collaborator: Genentech, Inc. (Industry), Merck Sharp & Dohme LLC (Industry)
• Enrollment: 48
• Location: 1
• Arm: 1
• Duration (Months): 37
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

It has been shown that bevacizumab has significant anti-tumor activity in patients with recurrent glioblastoma multiforme. Vorinostat has modest anti-tumor activity against malignant glioma and can enhance the action of both chemotherapy and anti-angiogenics. Patients will be treated with a combination of bevacizumab and vorinostat.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Glioblastoma Multiforme; Malignant Glioma; Adult Brain Tumor	Drug: Vorinostat; Drug: Bevacizumab	Phase 2

Detailed Description

There is no effective therapy for patients with recurrent glioblastoma multiforme (GBM) hence such patients remain a major unmet need in oncology. The investigators have recently demonstrated that bevacizumab (BV), a humanized monoclonal antibody against vascular endothelial growth factor, has significant anti-tumor activity among recurrent glioblastoma multiforme patients. Vorinostat has modest anti-tumor activity against malignant glioma and can potentiate the action of both chemotherapy and anti-angiogenics. The current study is designed to evaluate the anti-tumor activity of vorinostat when combined with BV among recurrent glioblastoma multiforme patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Bevacizumab and Vorinostat for Recurrent WHO Grade IV Malignant Glioma Patients
• Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vorinostat & Bevacizumab Patients will be administered bevacizumab every 2 weeks and vorinostat will be taken on days 1-7 and 15-21 of each 28-day cycle at 400 mg per day.	Drug: Vorinostat; Other Names: SAHA ; Drug: Bevacizumab; Other Names: Avastin

Outcome Measures

Primary Outcome Measures

1. Six-month Progression-free Survival (PFS6) [6 months]

   The percentage of participants alive and progression-free at 6 months after the start of study treatment will be determined. Based on Response Assessment in Neuro-Oncology (RANO) criteria, progression is defined as a ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; significant increase in T2/FLAIR; any new lesion; clear clinical deterioration not attributable to other causes apart from the tumor; failure to return for evaluation as a result of death or deteriorating condition; or clear progression of non-measurable disease. PFS6 will be calculated from the date study treatment started until the date of progression or death, or the date of last follow-up if participants are alive without progression. Kaplan-Meier methods will be used to estimate survival.

Secondary Outcome Measures

1. Radiographic Response [3 Years]

   The percentage of participants with a complete or partial response as determined by modified Response Assessment in Neuro-Oncology (RANO) criteria will be determined. Complete Response (CR) is defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses) and accompanied by a stable or improving neurologic examination. Partial Response (PR) is defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids and accompanied by a stable or improving neurologic examination. Tumor assessments are done at baseline and the end of every second cycle (every 8 weeks) thereafter.

2. Percentage of Participants Who Experience Grade 3 or Greater, Treatment Related, Non-hematologic Toxicities. [2.7 Years]

   The percentage of participants who experience grade 3 or greater, treatment-related, non-hematologic toxicities will be calculated.

3. Median Progression-free Survival (PFS) [3 Years]

   Progression-free survival is defined as the time in months from the start of protocol treatment until the date of progression or death if death occurred before progression. If the participant is alive and progression-free, PFS will be censored at the date of last follow-up. Kaplan-Meier methods will be used to estimate progression-free survival.

4. Median Overall Survival (OS) [3 Years]

   Overall survival is defined as the time in months from the start of protocol treatment until the date of death, or the date of last follow-up if alive. Kaplan-Meier methods will be used to estimate overall survival.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age > 18 years.

• An interval of at least 4 weeks between prior surgical resection or one week from stereotactic biopsy.

• An interval of at least 12 weeks from the end of prior radiotherapy unless there is a new area of enhancement consistent with recurrent tumor outside of the radiation field, or there is biopsy-proven tumor progression

• An interval of at least 4 weeks from prior chemotherapy [6 weeks for nitrosoureas, 1 week for daily administered chemotherapy (metronomic dosing)] or investigational agent unless the patient has recovered from all anticipated toxicities associated with that therapy.

• Eastern Cooperative Oncology Group (ECOG) 0-1.

• Hematocrit ≥ 29%, hemoglobin ≥ 9, absolute neutrophil ≥1,500 cells/microliter, platelets ≥ 100,000 cells/microliters.

• Serum creatinine, serum glutamic oxaloacetic transaminase(SGOT) and bilirubin < 1.5 times upper limit of normal.

• Signed informed consent approved by the Institutional Review Board prior to patient entry.

• No evidence of hemorrhage on the baseline MRI or CT scan other than those that are stable grade 1.

• If sexually active, patients will take contraceptive measures for the duration of the treatments. Medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal ligation, hysterectomy, vasectomy), (2) approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD).

Exclusion Criteria:

Disease-specific exclusions

• More than 2 prior episodes of disease progression

• Prior therapy with histone deacetylase inhibitors; valproic acid is not permitted and patients previously treated with valproic acid must be off valproic acid for at least 30 days prior to initiation of study medication

• Prior bevacizumab therapy

• Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids

• Active infection requiring intravenous antibiotics

• Severe hepatic insufficiency, active viral hepatitis or HIV infection

• Requires therapeutic anti-coagulation with warfarin

General medical exclusions

Subjects meeting the following criteria are ineligible for study entry:

• Inability to comply with study and/or follow-up procedures

Bevacizumab-specific exclusions

• Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)

• Any prior history of hypertensive crisis or hypertensive encephalopathy

• New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E)

• History of myocardial infarction or unstable angina within 6 months prior to study enrollment

• History of stroke or transient ischemic attack within 6 months prior to study enrollment

• Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

• Symptomatic peripheral vascular disease

• Evidence of bleeding diathesis or coagulopathy

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study

• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment

• Serious, non-healing wound, ulcer, or bone fracture

• Proteinuria at screening as demonstrated by either:

• Urine protein:creatinine (UPC) ratio >= 1.0 at screening OR

• Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).

• Known hypersensitivity to any component of bevacizumab

• Pregnant (positive pregnancy test) or lactating. Refuse the use of effective means of contraception (men and women) in subjects of child-bearing potential

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke Cancer Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Duke University
• Genentech, Inc.
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Katherine Peters, MD, PhD, Duke University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Link to the Preston Robert Tisch Brain Tumor Center
• Duke Cancer Institute
• Duke Cancer Center - Patient Care

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT01738646
• Other Study ID Numbers: Pro00024983
• First Posted: Nov 30, 2012
• Last Update Posted: Mar 6, 2017
• Last Verified: Nov 1, 2016

• Keywords provided by Duke University: vorinostat; SAHA; bevacizumab; AVASTIN; malignant glioma; GBM; glioblastoma multiforme; brain tumor
• Additional relevant MeSH terms: Glioblastoma; Glioma; Brain Neoplasms; Recurrence; Bevacizumab; Vorinostat

Study Results

Participant Flow

Pre-assignment Detail	48 participants signed consent. 8 participants are considered screen failures. 40 participants received treatment.

Arm/Group Title	Vorinostat & Bevacizumab
Arm/Group Description	Patients will be administered bevacizumab every 2 weeks and vorinostat will be taken on days 1-7 and 15-21 of each 28-day cycle at 400 mg per day.
Period Title: Overall Study
STARTED	40
COMPLETED	38
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Vorinostat & Bevacizumab
Arm/Group Description	Patients will be administered bevacizumab every 2 weeks and vorinostat will be taken on days 1-7 and 15-21 of each 28-day cycle at 400 mg per day.
Overall Participants	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.4 (11.0)
Sex: Female, Male (Count of Participants)
Female	16 40%
Male	24 60%

Outcome Measures

1. Primary Outcome

Title	Six-month Progression-free Survival (PFS6)
Description	The percentage of participants alive and progression-free at 6 months after the start of study treatment will be determined. Based on Response Assessment in Neuro-Oncology (RANO) criteria, progression is defined as a ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions; significant increase in T2/FLAIR; any new lesion; clear clinical deterioration not attributable to other causes apart from the tumor; failure to return for evaluation as a result of death or deteriorating condition; or clear progression of non-measurable disease. PFS6 will be calculated from the date study treatment started until the date of progression or death, or the date of last follow-up if participants are alive without progression. Kaplan-Meier methods will be used to estimate survival.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Vorinostat & Bevacizumab
Arm/Group Description	Patients will be administered bevacizumab every 2 weeks and vorinostat will be taken on days 1-7 and 15-21 of each 28-day cycle at 400 mg per day.
Measure Participants	40
Number (95% Confidence Interval) [percentage of participants]	30 75%

2. Secondary Outcome

Title	Radiographic Response
Description	The percentage of participants with a complete or partial response as determined by modified Response Assessment in Neuro-Oncology (RANO) criteria will be determined. Complete Response (CR) is defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses) and accompanied by a stable or improving neurologic examination. Partial Response (PR) is defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids and accompanied by a stable or improving neurologic examination. Tumor assessments are done at baseline and the end of every second cycle (every 8 weeks) thereafter.
Time Frame	3 Years

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Vorinostat & Bevacizumab
Arm/Group Description	Patients will be administered bevacizumab every 2 weeks and vorinostat will be taken on days 1-7 and 15-21 of each 28-day cycle at 400 mg per day. Vorinostat Bevacizumab
Measure Participants	40
Number (95% Confidence Interval) [percentage of participants]	22.5 56.3%

3. Secondary Outcome

Title	Percentage of Participants Who Experience Grade 3 or Greater, Treatment Related, Non-hematologic Toxicities.
Description	The percentage of participants who experience grade 3 or greater, treatment-related, non-hematologic toxicities will be calculated.
Time Frame	2.7 Years

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Vorinostat & Bevacizumab
Arm/Group Description	Patients will be administered bevacizumab every 2 weeks and vorinostat will be taken on days 1-7 and 15-21 of each 28-day cycle at 400 mg per day.
Measure Participants	40
Number [percentage of participants]	40 100%

4. Secondary Outcome

Title	Median Progression-free Survival (PFS)
Description	Progression-free survival is defined as the time in months from the start of protocol treatment until the date of progression or death if death occurred before progression. If the participant is alive and progression-free, PFS will be censored at the date of last follow-up. Kaplan-Meier methods will be used to estimate progression-free survival.
Time Frame	3 Years

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Vorinostat & Bevacizumab
Arm/Group Description	Patients will be administered bevacizumab every 2 weeks and vorinostat will be taken on days 1-7 and 15-21 of each 28-day cycle at 400 mg per day.
Measure Participants	40
Median (95% Confidence Interval) [months]	3.7

5. Secondary Outcome

Title	Median Overall Survival (OS)
Description	Overall survival is defined as the time in months from the start of protocol treatment until the date of death, or the date of last follow-up if alive. Kaplan-Meier methods will be used to estimate overall survival.
Time Frame	3 Years

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Vorinostat & Bevacizumab
Arm/Group Description	Patients will be administered bevacizumab every 2 weeks and vorinostat will be taken on days 1-7 and 15-21 of each 28-day cycle at 400 mg per day.
Measure Participants	40
Median (95% Confidence Interval) [months]	10.4

Adverse Events

Time Frame	From the start of study treatment for a patient until 30 days after treatment is discontinued.
Adverse Event Reporting Description	Patients will be evaluated for adverse events (AEs) (all grades), serious AEs, and adverse events requiring study drug interruption or discontinuation at each study visit for the duration of their participation in the study.
Arm/Group Title	Vorinostat & Bevacizumab
Arm/Group Description	Patients will be evaluated for adverse events (all grades), serious adverse events, and adverse events requiring study drug interruption or discontinuation at each study visit for the duration of their participation in the study.
All Cause Mortality
	Vorinostat & Bevacizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Vorinostat & Bevacizumab
	Affected / at Risk (%)	# Events
Total	12/40 (30%)
Cardiac disorders
Sinus bradycardia	2/40 (5%)
Gastrointestinal disorders
Constipation	1/40 (2.5%)
Enterocolitis	1/40 (2.5%)
Nausea	1/40 (2.5%)
General disorders
Death NOS	2/40 (5%)
Fatigue	1/40 (2.5%)
Fever	1/40 (2.5%)
Malaise	1/40 (2.5%)
Infections and infestations
Lung infection	1/40 (2.5%)
Injury, poisoning and procedural complications
Fall	1/40 (2.5%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	3/40 (7.5%)
Nervous system disorders
Edema cerebral	1/40 (2.5%)
Intracranial hemorrhage	1/40 (2.5%)
Pyramidal tract syndrome	1/40 (2.5%)
Seizure	7/40 (17.5%)
Psychiatric disorders
Confusion	1/40 (2.5%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/40 (2.5%)
Vascular disorders
Thromboembolic event	2/40 (5%)
Other (Not Including Serious) Adverse Events
	Vorinostat & Bevacizumab
	Affected / at Risk (%)	# Events
Total	40/40 (100%)
Blood and lymphatic system disorders
Anemia	15/40 (37.5%)
Cardiac disorders
Sinus bradycardia	5/40 (12.5%)
Ear and labyrinth disorders
Ear pain	1/40 (2.5%)
Eye disorders
Blurred vision	3/40 (7.5%)
Conjunctivitis	1/40 (2.5%)
Gastrointestinal disorders
Abdominal pain	1/40 (2.5%)
Anal hemorrhage	1/40 (2.5%)
Bloating	2/40 (5%)
Constipation	11/40 (27.5%)
Dental caries	1/40 (2.5%)
Diarrhea	28/40 (70%)
Dry mouth	1/40 (2.5%)
Dysphagia	1/40 (2.5%)
Gastroesophageal reflux disease	1/40 (2.5%)
Gastrointestinal disorders - Other, specify	1/40 (2.5%)
Mucositis oral	3/40 (7.5%)
Nausea	17/40 (42.5%)
Vomiting	6/40 (15%)
General disorders
Edema limbs	1/40 (2.5%)
Fatigue	28/40 (70%)
Pain	1/40 (2.5%)
Infections and infestations
Bronchial infection	1/40 (2.5%)
Infections and infestations - Other, specify	2/40 (5%)
Laryngitis	1/40 (2.5%)
Paronychia	1/40 (2.5%)
Sinusitis	4/40 (10%)
Skin infection	2/40 (5%)
Upper respiratory infection	6/40 (15%)
Urinary tract infection	3/40 (7.5%)
Wound infection	1/40 (2.5%)
Injury, poisoning and procedural complications
Bruising	2/40 (5%)
Fall	1/40 (2.5%)
Investigations
Alanine aminotransferase increased	9/40 (22.5%)
Alkaline phosphatase increased	3/40 (7.5%)
Aspartate aminotransferase increased	9/40 (22.5%)
Blood bilirubin increased	1/40 (2.5%)
Creatinine increased	9/40 (22.5%)
Lymphocyte count decreased	32/40 (80%)
Neutrophil count decreased	22/40 (55%)
Platelet count decreased	33/40 (82.5%)
Weight loss	2/40 (5%)
White blood cell decreased	27/40 (67.5%)
Metabolism and nutrition disorders
Anorexia	5/40 (12.5%)
Dehydration	1/40 (2.5%)
Hyperglycemia	27/40 (67.5%)
Hyperkalemia	2/40 (5%)
Hypernatremia	5/40 (12.5%)
Hypoalbuminemia	1/40 (2.5%)
Hypocalcemia	10/40 (25%)
Hypoglycemia	4/40 (10%)
Hypokalemia	8/40 (20%)
Hyponatremia	11/40 (27.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	10/40 (25%)
Back pain	3/40 (7.5%)
Generalized muscle weakness	2/40 (5%)
Muscle weakness upper limb	1/40 (2.5%)
Myalgia	3/40 (7.5%)
Pain in extremity	1/40 (2.5%)
Nervous system disorders
Dizziness	2/40 (5%)
Dysgeusia	5/40 (12.5%)
Dysphasia	4/40 (10%)
Headache	17/40 (42.5%)
Memory impairment	6/40 (15%)
Paresthesia	2/40 (5%)
Pyramidal tract syndrome	1/40 (2.5%)
Seizure	6/40 (15%)
Tremor	3/40 (7.5%)
Psychiatric disorders
Agitation	1/40 (2.5%)
Anxiety	1/40 (2.5%)
Delirium	1/40 (2.5%)
Insomnia	1/40 (2.5%)
Renal and urinary disorders
Proteinuria	13/40 (32.5%)
Renal and urinary disorders - Other, specify	2/40 (5%)
Urinary retention	2/40 (5%)
Reproductive system and breast disorders
Dyspareunia	1/40 (2.5%)
Erectile dysfunction	1/40 (2.5%)
Respiratory, thoracic and mediastinal disorders
Cough	2/40 (5%)
Epistaxis	6/40 (15%)
Hoarseness	9/40 (22.5%)
Nasal congestion	1/40 (2.5%)
Postnasal drip	12/40 (30%)
Sleep apnea	1/40 (2.5%)
Skin and subcutaneous tissue disorders
Alopecia	2/40 (5%)
Dry skin	9/40 (22.5%)
Rash acneiform	3/40 (7.5%)
Rash maculo-papular	1/40 (2.5%)
Skin and subcutaneous tissue disorders - Other, specify	3/40 (7.5%)
Vascular disorders
Hypertension	14/40 (35%)
Thromboembolic event	3/40 (7.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.