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Suberoylanilide Hydroxamic Acid (SAHA), Bevacizumab, Daily Temozolomide for Recurrent Malignant Gliomas

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ClinicalTrials.gov Identifier: NCT00939991
Recruitment Status : Completed
First Posted : July 15, 2009
Results First Posted : June 24, 2013
Last Update Posted : June 24, 2013
Sponsor:
Collaborators:
Genentech, Inc.
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Katy Peters, Duke University

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Brain Tumor
Glioblastoma
Intervention Drug: Vorinostst/Bevacizumab/Temozolomide
Enrollment 48
Recruitment Details Patients must have histologically confirmed diagnosis of malignant glioma (Grade 3 or 4 for Phase I and only Grade 4 for Phase II) and radiographic evidence of recurrence or disease progression following prior therapy.
Pre-assignment Details  
Arm/Group Title Phase I Dose Escalation Phase II
Hide Arm/Group Description Bevacizumab is to be administered intravenously at 10 mg/kg every other week starting on day 1. Temozolomide is to be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat (200mg/dose or 400mg/dose) is to be administered daily on days 1-7 and 15-21 of each 28 day cycle. The dose of Vorinostat is escalated in successive 3+3 cohorts of patients to determine the maximum tolerated dose (MTD) of this regimen. The MTD is the dose level at which 0/6 or 1/6 patients experience dose-limiting toxicity (DLT) with at least two patients experiencing DLT at the next higher dose level. Bevacizumab is to be administered intravenously at 10 mg/kg every other week. Temozolomide is to be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat is to be administered daily on days 1-7 and 15-21 of each 28 day cycle using the MTD from Phase I.
Period Title: Overall Study
Started 9 39
Completed 9 39
Not Completed 0 0
Arm/Group Title Phase I Dose Escalation Phase II Total
Hide Arm/Group Description Bevacizumab is to be administered intravenously at 10 mg/kg every other week starting on day 1. Temozolomide is to be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat (200mg/dose or 400mg/dose) is to be administered daily on days 1-7 and 15-21 of each 28 day cycle. The dose of Vorinostat is escalated in successive 3+3 cohorts of patients to determine the maximum tolerated dose (MTD) of this regimen. The MTD is the dose level at which 0/6 or 1/6 patients experience dose-limiting toxicity (DLT) with at least two patients experiencing DLT at the next higher dose level. Bevacizumab is to be administered intravenously at 10 mg/kg every other week. Temozolomide is to be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat is to be administered daily on days 1-7 and 15-21 of each 28 day cycle using the MTD from Phase I. Total of all reporting groups
Overall Number of Baseline Participants 9 39 48
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 9 participants 39 participants 48 participants
47  (14) 51  (11) 50  (12)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 39 participants 48 participants
Female
3
  33.3%
12
  30.8%
15
  31.3%
Male
6
  66.7%
27
  69.2%
33
  68.8%
1.Primary Outcome
Title Phase I: Determination of the Maximum Tolerated Dose (MTD)
Hide Description The MTD is based upon dose-limiting toxicities (DLTs) experienced during Cycle 1 of treatment. The MTD is the dose level at which 0/6 or 1/6 patients experience DLT with at least two patients experiencing DLT at the next higher dose level. Using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, DLTs are defined as: Grade 4 neutropenia lasting greater than 5 days; Grade 3 thrombocytopenia; the occurrence of non-hematologic Grade 3 or greater drug-related adverse events excluding Grade ≥ 3 elevation in alkaline phosphatase, Grade ≥ 3 nausea or vomiting unless occurring despite the use of standard anti-emetics or Grade 3 diarrhea unless occurring despite standard anti-diarrheal therapy; > 14 day delay to re-treat due to failure to resolve drug-related toxicity to re-treatment criteria or pre-treatment baseline.
Time Frame Cycle 1 (28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase I Dose Escalation
Hide Arm/Group Description:
Bevacizumab is to be administered intravenously at 10 mg/kg every other week starting on day 1. Temozolomide is to be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat (200mg/dose or 400mg/dose) is to be administered daily on days 1-7 and 15-21 of each 28 day cycle. The dose of Vorinostat is escalated in successive 3+3 cohorts of patients to determine the maximum tolerated dose (MTD) of this regimen. The MTD is the dose level at which 0/6 or 1/6 patients experience dose-limiting toxicity (DLT) with at least two patients experiencing DLT at the next higher dose level.
Overall Number of Participants Analyzed 9
Measure Type: Number
Unit of Measure: mg
400
2.Primary Outcome
Title Phase II: 6-month Progression-free Survival (PFS)
Hide Description Phase II: Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to RANO criteria, or to death due to any cause. Per RANO, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion or clinical deterioration.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase II
Hide Arm/Group Description:
Bevacizumab is to be administered intravenously at 10 mg/kg every other week. Temozolomide is to be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat is to be administered daily on days 1-7 and 15-21 of each 28 day cycle using the MTD from Phase I.
Overall Number of Participants Analyzed 39
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
53.8
(37.2 to 67.9)
3.Secondary Outcome
Title Phase II: Radiographic Response.
Hide Description The percentage of participants with a complete or partial response as determined by modified Response Assessment in Neuro-Oncology (RANO) criteria. A confirmation of response was not required. Complete Response (CR) was 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) was 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 were done at baseline, the end of the first cycle (4 weeks), then the end of every second cycle (every 8 weeks) thereafter.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase II
Hide Arm/Group Description:
Bevacizumab is to be administered intravenously at 10 mg/kg every other week. Temozolomide is to be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat is to be administered daily on days 1-7 and 15-21 of each 28 day cycle using the MTD from Phase I.
Overall Number of Participants Analyzed 39
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
56
(41 to 71)
4.Secondary Outcome
Title Phase II: Median Progression-free Survival (PFS)
Hide Description Phase II: Time in months from the start of study treatment to the date of first progression according to RANO criteria, or to death due to any cause. Per RANO, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion or clinical deterioration. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase II
Hide Arm/Group Description:
Bevacizumab is to be administered intravenously at 10 mg/kg every other week. Temozolomide is to be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat is to be administered daily on days 1-7 and 15-21 of each 28 day cycle using the MTD from Phase I.
Overall Number of Participants Analyzed 39
Median (95% Confidence Interval)
Unit of Measure: months
6.7
(4.8 to 9.4)
5.Secondary Outcome
Title Phase II: Median Overall Survival (OS)
Hide Description Phase II: Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase II
Hide Arm/Group Description:
Bevacizumab is to be administered intravenously at 10 mg/kg every other week. Temozolomide is to be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat is to be administered daily on days 1-7 and 15-21 of each 28 day cycle using the MTD from Phase I.
Overall Number of Participants Analyzed 39
Median (95% Confidence Interval)
Unit of Measure: months
12.5
(8.8 to 14.3)
6.Secondary Outcome
Title Phase II: Number of Patients With Grade 2 or Greater, Treatment-related Toxicities
Hide Description Phase II: Number of patients with grade 2 or greater, treatment-related toxicities based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase II
Hide Arm/Group Description:
Bevacizumab is to be administered intravenously at 10 mg/kg every other week. Temozolomide is to be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat is to be administered daily on days 1-7 and 15-21 of each 28 day cycle using the MTD from Phase I.
Overall Number of Participants Analyzed 39
Measure Type: Number
Unit of Measure: participants
33
Time Frame 3 years
Adverse Event Reporting Description The adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and have been converted to CTCAE version 4.0 for entry into ClinicalTrials.gov.
 
Arm/Group Title Phase I Dose Escalation Phase II
Hide Arm/Group Description Bevacizumab is to be administered intravenously at 10 mg/kg every other week starting on day 1. Temozolomide is to be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat (200mg/dose or 400mg/dose) is to be administered daily on days 1-7 and 15-21 of each 28 day cycle. The dose of Vorinostat is escalated in successive 3+3 cohorts of patients to determine the maximum tolerated dose (MTD) of this regimen. The MTD is the dose level at which 0/6 or 1/6 patients experience dose-limiting toxicity (DLT) with at least two patients experiencing DLT at the next higher dose level. Bevacizumab is to be administered intravenously at 10 mg/kg every other week. Temozolomide is to be administered on a continuous daily dosing schedule at 50 mg/m2/day. Vorinostat is to be administered daily on days 1-7 and 15-21 of each 28 day cycle using the MTD from Phase I.
All-Cause Mortality
Phase I Dose Escalation Phase II
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Phase I Dose Escalation Phase II
Affected / at Risk (%) Affected / at Risk (%)
Total   0/9 (0.00%)   5/39 (12.82%) 
Blood and lymphatic system disorders     
Anemia  1  0/9 (0.00%)  1/39 (2.56%) 
Eye disorders     
Extraocular muscle paresis  1  0/9 (0.00%)  1/39 (2.56%) 
Gastrointestinal disorders     
Small intestinal perforation  1  0/9 (0.00%)  1/39 (2.56%) 
General disorders     
Chills  1  0/9 (0.00%)  1/39 (2.56%) 
Infections and infestations     
Infections and infestations - Other, specify  1  0/9 (0.00%)  3/39 (7.69%) 
Injury, poisoning and procedural complications     
Fracture  1  0/9 (0.00%)  1/39 (2.56%) 
Vascular access complication  1  0/9 (0.00%)  1/39 (2.56%) 
Metabolism and nutrition disorders     
Hypokalemia  1  0/9 (0.00%)  1/39 (2.56%) 
Hypophosphatemia  1  0/9 (0.00%)  1/39 (2.56%) 
Nervous system disorders     
Intracranial hemorrhage  1  0/9 (0.00%)  1/39 (2.56%) 
Ischemia cerebrovascular  1  0/9 (0.00%)  1/39 (2.56%) 
Seizure  1  0/9 (0.00%)  2/39 (5.13%) 
Respiratory, thoracic and mediastinal disorders     
Hypoxia  1  0/9 (0.00%)  1/39 (2.56%) 
Vascular disorders     
Thromboembolic event  1  0/9 (0.00%)  2/39 (5.13%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (4.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Phase I Dose Escalation Phase II
Affected / at Risk (%) Affected / at Risk (%)
Total   9/9 (100.00%)   39/39 (100.00%) 
Blood and lymphatic system disorders     
Anemia  1  6/9 (66.67%)  11/39 (28.21%) 
Cardiac disorders     
Cardiac disorders - Other, specify  1  1/9 (11.11%)  0/39 (0.00%) 
Palpitations  1  1/9 (11.11%)  0/39 (0.00%) 
Ear and labyrinth disorders     
Tinnitus  1  1/9 (11.11%)  1/39 (2.56%) 
Eye disorders     
Extraocular muscle paresis  1  1/9 (11.11%)  6/39 (15.38%) 
Eye disorders - Other, specify  1  0/9 (0.00%)  3/39 (7.69%) 
Gastrointestinal disorders     
Abdominal pain  1  2/9 (22.22%)  0/39 (0.00%) 
Constipation  1  7/9 (77.78%)  19/39 (48.72%) 
Diarrhea  1  5/9 (55.56%)  24/39 (61.54%) 
Dyspepsia  1  3/9 (33.33%)  0/39 (0.00%) 
Fecal incontinence  1  0/9 (0.00%)  2/39 (5.13%) 
Flatulence  1  1/9 (11.11%)  0/39 (0.00%) 
Gastritis  1  1/9 (11.11%)  3/39 (7.69%) 
Mucositis oral  1  1/9 (11.11%)  2/39 (5.13%) 
Nausea  1  6/9 (66.67%)  22/39 (56.41%) 
Vomiting  1  4/9 (44.44%)  8/39 (20.51%) 
General disorders     
Chills  1  0/9 (0.00%)  2/39 (5.13%) 
Edema limbs  1  1/9 (11.11%)  1/39 (2.56%) 
Fatigue  1  9/9 (100.00%)  32/39 (82.05%) 
Fever  1  0/9 (0.00%)  2/39 (5.13%) 
Gait disturbance  1  1/9 (11.11%)  4/39 (10.26%) 
Non-cardiac chest pain  1  1/9 (11.11%)  0/39 (0.00%) 
Pain  1  2/9 (22.22%)  4/39 (10.26%) 
Infections and infestations     
Infections and infestations - Other, specify  1  0/9 (0.00%)  6/39 (15.38%) 
Sinusitis  1  1/9 (11.11%)  4/39 (10.26%) 
Upper respiratory infection  1  1/9 (11.11%)  0/39 (0.00%) 
Urinary tract infection  1  1/9 (11.11%)  0/39 (0.00%) 
Investigations     
Alanine aminotransferase increased  1  3/9 (33.33%)  6/39 (15.38%) 
Alkaline phosphatase increased  1  2/9 (22.22%)  3/39 (7.69%) 
Aspartate aminotransferase increased  1  2/9 (22.22%)  9/39 (23.08%) 
Blood bilirubin increased  1  1/9 (11.11%)  7/39 (17.95%) 
Creatinine increased  1  3/9 (33.33%)  8/39 (20.51%) 
Neutrophil count decreased  1  5/9 (55.56%)  17/39 (43.59%) 
Platelet count decreased  1  8/9 (88.89%)  28/39 (71.79%) 
White blood cell decreased  1  7/9 (77.78%)  24/39 (61.54%) 
Metabolism and nutrition disorders     
Anorexia  1  1/9 (11.11%)  5/39 (12.82%) 
Dehydration  1  1/9 (11.11%)  2/39 (5.13%) 
Hyperglycemia  1  7/9 (77.78%)  23/39 (58.97%) 
Hyperkalemia  1  0/9 (0.00%)  3/39 (7.69%) 
Hypermagnesemia  1  1/9 (11.11%)  9/39 (23.08%) 
Hypernatremia  1  2/9 (22.22%)  2/39 (5.13%) 
Hypoalbuminemia  1  1/9 (11.11%)  8/39 (20.51%) 
Hypocalcemia  1  4/9 (44.44%)  16/39 (41.03%) 
Hypoglycemia  1  2/9 (22.22%)  3/39 (7.69%) 
Hypokalemia  1  3/9 (33.33%)  6/39 (15.38%) 
Hyponatremia  1  1/9 (11.11%)  13/39 (33.33%) 
Hypophosphatemia  1  4/9 (44.44%)  4/39 (10.26%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/9 (11.11%)  2/39 (5.13%) 
Back pain  1  2/9 (22.22%)  2/39 (5.13%) 
Muscle weakness lower limb  1  1/9 (11.11%)  1/39 (2.56%) 
Muscle weakness right-sided  1  1/9 (11.11%)  0/39 (0.00%) 
Muscle weakness upper limb  1  1/9 (11.11%)  2/39 (5.13%) 
Musculoskeletal and connective tissue disorder - Other, specify  1  1/9 (11.11%)  1/39 (2.56%) 
Myalgia  1  0/9 (0.00%)  2/39 (5.13%) 
Pain in extremity  1  2/9 (22.22%)  1/39 (2.56%) 
Nervous system disorders     
Ataxia  1  1/9 (11.11%)  5/39 (12.82%) 
Cognitive disturbance  1  1/9 (11.11%)  0/39 (0.00%) 
Dizziness  1  1/9 (11.11%)  1/39 (2.56%) 
Dysgeusia  1  1/9 (11.11%)  0/39 (0.00%) 
Dysphasia  1  2/9 (22.22%)  5/39 (12.82%) 
Headache  1  7/9 (77.78%)  13/39 (33.33%) 
Memory impairment  1  1/9 (11.11%)  5/39 (12.82%) 
Peripheral sensory neuropathy  1  0/9 (0.00%)  4/39 (10.26%) 
Seizure  1  4/9 (44.44%)  2/39 (5.13%) 
Tremor  1  2/9 (22.22%)  0/39 (0.00%) 
Psychiatric disorders     
Agitation  1  2/9 (22.22%)  2/39 (5.13%) 
Anxiety  1  0/9 (0.00%)  2/39 (5.13%) 
Confusion  1  1/9 (11.11%)  2/39 (5.13%) 
Delayed orgasm  1  1/9 (11.11%)  0/39 (0.00%) 
Depression  1  2/9 (22.22%)  2/39 (5.13%) 
Insomnia  1  2/9 (22.22%)  3/39 (7.69%) 
Psychosis  1  1/9 (11.11%)  0/39 (0.00%) 
Renal and urinary disorders     
Hematuria  1  1/9 (11.11%)  0/39 (0.00%) 
Proteinuria  1  5/9 (55.56%)  16/39 (41.03%) 
Urinary incontinence  1  2/9 (22.22%)  3/39 (7.69%) 
Respiratory, thoracic and mediastinal disorders     
Allergic rhinitis  1  2/9 (22.22%)  2/39 (5.13%) 
Cough  1  2/9 (22.22%)  3/39 (7.69%) 
Dyspnea  1  1/9 (11.11%)  3/39 (7.69%) 
Epistaxis  1  3/9 (33.33%)  2/39 (5.13%) 
Pharyngolaryngeal pain  1  1/9 (11.11%)  3/39 (7.69%) 
Respiratory, thoracic and mediastinal disorders - Other, specify  1  1/9 (11.11%)  0/39 (0.00%) 
Voice alteration  1  3/9 (33.33%)  3/39 (7.69%) 
Skin and subcutaneous tissue disorders     
Dry skin  1  2/9 (22.22%)  1/39 (2.56%) 
Pruritus  1  0/9 (0.00%)  2/39 (5.13%) 
Rash acneiform  1  2/9 (22.22%)  4/39 (10.26%) 
Skin and subcutaneous tissue disorders - Other, specify  1  0/9 (0.00%)  2/39 (5.13%) 
Vascular disorders     
Hypertension  1  5/9 (55.56%)  8/39 (20.51%) 
Hypotension  1  1/9 (11.11%)  0/39 (0.00%) 
Thromboembolic event  1  0/9 (0.00%)  3/39 (7.69%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (4.0)
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Katherine Peters, MD, PhD
Organization: Duke University Medical Center
Phone: 919-684-3914
Responsible Party: Katy Peters, Duke University
ClinicalTrials.gov Identifier: NCT00939991     History of Changes
Other Study ID Numbers: Pro00016446
First Submitted: July 14, 2009
First Posted: July 15, 2009
Results First Submitted: May 3, 2013
Results First Posted: June 24, 2013
Last Update Posted: June 24, 2013