Optune(NOVOTTF-100A)+ Bevacizumab+ Hypofractionated Stereotactic Irradiation Bevacizumab-Naive Recurrent Glioblastoma (GCC 1344)

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01925573
• Collaborator: NovoCure Ltd. (Industry)
• Enrollment: 7
• Location: 1
• Arm: 1
• Actual Duration (Months): 63
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This protocol is designed to generate and provide preliminary data to determine the safety and activity of combination therapy using tumor treating fields (TTFields; Optune(NovoTTF-100A); Novocure, Haifa, Israel), a novel FDA-approved therapy utilizing alternating electric fields to inhibit tumor cell growth, along with bevacizumab (Avastin; Genentech, San Francisco, CA), a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), and hypofractionated stereotactic radiotherapy, a highly-focal abbreviated course of brain irradiation, in the treatment of patients with bevacizumab-naive recurrent GBM. Each of these individual therapies, and also several combinations in doublets, has already demonstrated safety and efficacy but prospective clinical data for the concurrent combination of all three therapies are lacking.

Condition or Disease	Intervention/Treatment	Phase
RECURRENT GLIOBLASTOMA; Brain Tumor	Device: Optune(NOVOTTF-100A)	N/A

Detailed Description

The combination of Optune(NovoTTF) with the active regimen of bevacizumab and hypofractionated stereotactic radiotherapy bases the addition of an effective new treatment in the setting of a safe regimen with favorable survival reports. To date, no clinical data are available on the interaction of concomitant tumor treating fields with radiation therapy either with or without bevacizumab. TTF and radiation both have the potential to enhance the other's therapeutic ratio though synergistic mechanisms of action. The addition of bevacizumab to this regimen has both therapeutic and improved-toxicity implications. A trial combining Optune with the proven regimen of HFSRT and bevacizumab for recurrent glioblastoma affords an avenue to demonstrate safety in a population who may more readily derive a benefit from novel multimodality therapy and explore the potential for synergistic effect. The endpoint of efficacy would clearly need to be more definitively addressed in a future categorical trial, which would be the logical positive outcome of this pilot study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Proposed Pilot Study of Combined Optune+ Bevacizumab, and Hypofractionated Stereotactic Irradiation for Bevacizumab-Naive Recurrent Glioblastoma
• Actual Study Start Date: May 1, 2014
• Actual Primary Completion Date: Aug 1, 2019
• Actual Study Completion Date: Aug 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Other: Optune+RT+Bevacuzimab Part 1: Bevacizumab every 2 weeks plus Optune daily for 4 week cycles. Part 2: RT will begin post 3 round of Bevacizumab (hypofractionated radiotherapy: 30 Gy in 5 fractions or 35 Gy in 10 fractions) per physician choice. Part 3: Adjuvant Bevacizumab and Optune	Device: Optune(NOVOTTF-100A)

Outcome Measures

Primary Outcome Measures

1. Number of Participants With a Grade 3 or High Toxicity/Adverse Event (Primary Measure) [6 months]

   The ability to complete protocol treatment (i.e. tri-modality treatment) without undue acute toxicity as defined below : <40% rate of Grade 3 or higher nonhematologic toxicity. : <15% rate of Grade 4 or higher nonhematologic toxicity : <5% rate of Grade 4+ scalp dermatitis : <50% rate of Grade 2-3 scalp dermatitis Early stopping rules: Two or more Grade 2 or higher symptomatic CNS hemorrhages; Eight treatment-related Grade 3 or higher non hematologic or Grade 4 or higher hematologic toxicities.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 22 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 1 Patients with recurrent or progressive glioblastoma or other grade IV malignant glioma (i.e. glioblastoma, gliosarcoma, giant cell glioblastoma, etc.) who have failed prior radiation but who have not progressed/recurred on bevacizumab. Patients will be eligible if the original histology was lower-grade glioma and subsequent diagnosis of glioblastoma or gliosarcoma is made.

2 Patients with any number of recurrences are allowed. 3 Brain MRI demonstrates an enhancing tumor < 8 cm in largest diameter. 4 Karnofsky performance status ≥ 70%. 5

Age ≥ 22 years old. 6 Patients must have the following laboratory values:

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

• Platelets ≥ 100 x 109/L

• Hemoglobin (Hgb) > 10 g/dL

• Serum total bilirubin: ≤ 1.5 x ULN

• ALT and AST ≤ 3.0 x ULN

• Adequate Renal Function: BUN and Cr < 2.0 x ULN

• Blood coagulation parameters: international normalized ratio (INR) ≤ 1.5 for patients not on warfarin 7 Minimum interval since completion of radiation treatment is 12 weeks. 8 History of standard dose CNS radiotherapy: radiation of 60 Gy in 30 fractions or 59.4 Gy in 1.8 Gy fractions, or equivalent or lower doses.

9 Minimum interval since last major surgery, open biopsy, or significant traumatic injury is 4 weeks 10 Minimum interval since last drug therapy:

• 3 weeks since last non-cytotoxic therapy

• 3 weeks must have elapsed since the completion of a non-nitrosourea-containing chemotherapy regimen

• 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen. 11 Patients must have signed an approved informed consent and authorization permitting release of personal health information.

12 Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. Female patients of child-bearing potential must have a negative pregnancy test.

13 Patients with history of prior invasive malignancy (except non-melanomatous skin cancer) must have been disease free for a minimum of 1 year.

14 Patients must be maintained on a stable corticosteroid regimen from the time of their baseline scan until the start of treatment and/or for at least 5 days before starting treatment.

15 Patients on full-dose anticoagulants (e.g., warfarin or LMW heparin) must meet both of the following criteria: 16 No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices) 17 In-range INR (max ≤ 3) on a stable dose of oral anticoagulant for greater than 1 month or on a stable dose of low molecular weight heparin

Exclusion Criteria:

• 1 Any prior therapy with bevacizumab 2 Any significant hemorrhage defined as > 1 cm diameter of blood seen on the MRI or CT scan. If > 1 cm of acute blood is detected, the patient will be ineligible for this trial.

3 Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury.

4 Patients with impaired cardiac function or clinically significant cardiac diseases, including any of the following:

• History or presence of serious uncontrolled ventricular arrhythmias

• Any of the following within 6 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE)

• Uncontrolled hypertension (defined by a SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg while on anti-hypertensive medications) or history of hypertensive crisis or hypertensive encephalopathy, stroke, TIA, symptomatic peripheral vascular disease, or grade 2 CHF 5 Patients with cirrhosis, or active viral or non-viral hepatitis. 6 Patients with peptic ulcer, abdominal fistula, gastrointestinal perforation, intra-abdominal abscess within 6 months of enrollment.

7 Implanted pacemaker, defibrillator or deep brain stimulator, other implanted electronic devices in the brain or documented clinically significant arrhythmias.

8 Infra-tentorial tumor. 9 Known sensitivity to conductive hydrogels. 10 Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory).

11 Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol 12 Pregnant or breast-feeding women. 13 Patients unwilling or unable to comply with the protocol. 14 Patients treated on any other therapeutic clinical protocols within 3 weeks of starting on this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ummc Msgcc	Baltimore	Maryland	United States	21201

Sponsors and Collaborators

• University of Maryland, Baltimore
• NovoCure Ltd.

Investigators

• Principal Investigator: Kwok Young, MD, University of Maryland, Baltimore

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 1, 2018

More Information

Publications

None provided.

• Responsible Party: Department of Radiation Oncology, Principal Investigator, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT01925573
• Other Study ID Numbers: HP-00056719
• First Posted: Aug 19, 2013
• Last Update Posted: Feb 3, 2022
• Last Verified: Jan 1, 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Department of Radiation Oncology, Principal Investigator, University of Maryland, Baltimore: RECURRENT GLIOBLASTOMA; Brain Tumor
• Additional relevant MeSH terms: Glioblastoma; Brain Neoplasms; Recurrence

Study Results

Participant Flow

Arm/Group Title	Optune+RT+Bevacuzimab
Arm/Group Description	Part 1: Bevacizumab every 2 weeks plus Optune daily for 4 week cycles. Part 2: RT will begin post 3 round of Bevacizumab (hypofractionated radiotherapy: 30 Gy in 5 fractions or 35 Gy in 10 fractions) per physician choice. Part 3: Adjuvant Bevacizumab and Optune Optune(NOVOTTF-100A)
Period Title: Overall Study
STARTED	7
COMPLETED	0
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Optune+RT+Bevacuzimab
Arm/Group Description	Part 1: Bevacizumab every 2 weeks plus Optune daily for 4 week cycles. Part 2: RT will begin post 3 round of Bevacizumab (hypofractionated radiotherapy: 30 Gy in 5 fractions or 35 Gy in 10 fractions) per physician choice. Part 3: Adjuvant Bevacizumab and Optune Optune(NOVOTTF-100A)
Overall Participants	7
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	4 57.1%
>=65 years	3 42.9%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	59.7
Sex: Female, Male (Count of Participants)
Female	3 42.9%
Male	4 57.1%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	5 71.4%
African American	1 14.3%
Asian	1 14.3%
Region of Enrollment (participants) [Number]
United States	7 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With a Grade 3 or High Toxicity/Adverse Event (Primary Measure)
Description	The ability to complete protocol treatment (i.e. tri-modality treatment) without undue acute toxicity as defined below : <40% rate of Grade 3 or higher nonhematologic toxicity. : <15% rate of Grade 4 or higher nonhematologic toxicity : <5% rate of Grade 4+ scalp dermatitis : <50% rate of Grade 2-3 scalp dermatitis Early stopping rules: Two or more Grade 2 or higher symptomatic CNS hemorrhages; Eight treatment-related Grade 3 or higher non hematologic or Grade 4 or higher hematologic toxicities.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Optune+RT+Bevacuzimab
Arm/Group Description	Part 1: Bevacizumab every 2 weeks plus Optune daily for 4 week cycles. Part 2: RT will begin post 3 round of Bevacizumab (hypofractionated radiotherapy: 30 Gy in 5 fractions or 35 Gy in 10 fractions) per physician choice. Part 3: Adjuvant Bevacizumab and Optune Optune(NOVOTTF-100A)
Measure Participants	7
Count of Participants [Participants]	7 100%

Adverse Events

Time Frame	AEs were evaluated per protocol during radiation and chemo, as well as during the follow-up period. Radiation and concurrent chemo lasted 6-7 weeks. Adjuvant chemo lasted 6-12 months after completion of radiation.
Adverse Event Reporting Description	Systematic assessment was done through regular physician assessments.
Arm/Group Title	Optune+RT+Bevacuzimab
Arm/Group Description	Part 1: Bevacizumab every 2 weeks plus Optune daily for 4 week cycles. Part 2: RT will begin post 3 round of Bevacizumab (hypofractionated radiotherapy: 30 Gy in 5 fractions or 35 Gy in 10 fractions) per physician choice. Part 3: Adjuvant Bevacizumab and Optune Optune(NOVOTTF-100A)
All Cause Mortality
	Optune+RT+Bevacuzimab
	Affected / at Risk (%)	# Events
Total	1/7 (14.3%)
Serious Adverse Events
	Optune+RT+Bevacuzimab
	Affected / at Risk (%)	# Events
Total	5/7 (71.4%)
Musculoskeletal and connective tissue disorders
Muscle Weakness	1/7 (14.3%)
Nervous system disorders
Encephalopathy	1/7 (14.3%)
Seizure	2/7 (28.6%)
Cranial- CN II Vision	1/7 (14.3%)
Vascular disorders
Hypertension	2/7 (28.6%)
Other (Not Including Serious) Adverse Events
	Optune+RT+Bevacuzimab
	Affected / at Risk (%)	# Events
Total	5/7 (71.4%)
Blood and lymphatic system disorders
Leukocytes (total WBC)	1/7 (14.3%)
Platelets	2/7 (28.6%)
Ear and labyrinth disorders
Tinnitus	1/7 (14.3%)
Eye disorders
Vision-blurred vision	1/7 (14.3%)
Gastrointestinal disorders
Constipation	1/7 (14.3%)
Dysphagia (difficulty swallowing)	1/7 (14.3%)
Taste alteration (dysgeusia)	1/7 (14.3%)
General disorders
Fatigue (asthenia, lethargy, malaise)	2/7 (28.6%)
Edema: limb	1/7 (14.3%)
Flu-like syndrome	1/7 (14.3%)
Investigations
Alkaline phosphatase	1/7 (14.3%)
Bilirubin (hyperbilirubinemia)	1/7 (14.3%)
Creatinine	2/7 (28.6%)
Metabolism and nutrition disorders
Anorexia	1/7 (14.3%)
Potassium, serum-high (hyperkalemia)	1/7 (14.3%)
Potassium, serum-low (hypokalemia)	1/7 (14.3%)
Sodium, serum-high (hypernatremia)	2/7 (28.6%)
Sodium, serum-low (hyponatremia)	1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Extremity-lower (gait/walking)	1/7 (14.3%)
Extremity-upper (function)	1/7 (14.3%)
Muscle weakness, generalized or specific area (not due to neuropathy) - Extremity-lower	1/7 (14.3%)
Muscle weakness, generalized or specific area (not due to neuropathy) - Facial	2/7 (28.6%)
Muscle weakness, generalized or specific area (not due to neuropathy) - Left-sided	2/7 (28.6%)
Muscle weakness, generalized or specific area (not due to neuropathy) - Left-sided	1/7 (14.3%)
Muscle weakness, generalized or specific area (not due to neuropathy) - Right-sided	1/7 (14.3%)
Pain - Back	1/7 (14.3%)
Pain - Joint	1/7 (14.3%)
Nervous system disorders
Ataxia (incoordination)	1/7 (14.3%)
Cognitive disturbance	1/7 (14.3%)
Confusion	2/7 (28.6%)
Dizziness	2/7 (28.6%)
Memory impairment	1/7 (14.3%)
Mental status	2/7 (28.6%)
Mental status	1/7 (14.3%)
Seizure	1/7 (14.3%)
Speech impairment (e.g., dysphasia or aphasia)	2/7 (28.6%)
Tremor	1/7 (14.3%)
Pain - Head/headache	1/7 (14.3%)
Psychiatric disorders
Mood alteration - Agitation	2/7 (28.6%)
Mood alteration - Anxiety	3/7 (42.9%)
Mood alteration - Anxiety	1/7 (14.3%)
Mood alteration - Depression	2/7 (28.6%)
Psychosis (hallucinations/delusions)	1/7 (14.3%)
Renal and urinary disorders
Urinary frequency/urgency	1/7 (14.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/7 (14.3%)
Dyspnea (shortness of breath)	1/7 (14.3%)
Skin and subcutaneous tissue disorders
Dermatology/Skin - Other (Specify, __)	1/7 (14.3%)
Hair loss/alopecia (scalp or body)	2/7 (28.6%)
Pruritus/itching	1/7 (14.3%)
Rash: dermatitis associated with radiation - Chemoradiation	1/7 (14.3%)
Rash: dermatitis associated with radiation - Radiation	1/7 (14.3%)
Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)	2/7 (28.6%)
Ulceration	1/7 (14.3%)
Vascular disorders
Hypertension	2/7 (28.6%)
Hypertension	3/7 (42.9%)
Hematoma	1/7 (14.3%)

Limitations/Caveats

Study was terminated due to poor accrual. No analysis was done due to having not met accrual for study analysis.

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.