GlioblastomaPhase 2NCT02743078
Optune® Plus Bevacizumab in Bevacizumab-Refractory Recurrent Glioblastoma
A Phase 2 study testing Bevacizumab and TTFields Therapy in people with Glioblastoma and Glioma, run by RTOG Foundation, Inc. at 11 sites in United States.
Trial summary
This phase II trial will investigate the efficacy and safety of the addition of Optune (Tumor Treating Fields [TTFields] Therapy) to bevacizumab for patients with bevacizumab-refractory recurrent glioblastoma. Read more about this study
- Who is it for?
- Ages 22 years and older
- Conditions the study is for
- Glioblastoma, Glioma, Gliosarcoma
- What is being tested?
- Bevacizumab and TTFields Therapy
- Type of treatment
- Injection or infusion, Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 11 sitesUnited States
- Study dates
- 9 May 2017to 15 Oct 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 22 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically proven diagnosis of glioblastoma or other grade IV malignant glioma (including variants of glioblastoma i.e., gliosarcoma, giant cell glioblastoma, etc.).
- Confirmation of tumor recurrence or progression on contrast magnetic resonance imaging (MRI) (with and without gadolinium contrast) as determined by Response assessment in neuro-oncology (RANO) criteria within 14 days prior to registration for patients who did not have recent resection of their glioblastoma or only had a stereotactic biopsy.
- Patients having undergone recent resection (within 5 weeks prior to registration) of their glioblastoma to treat current recurrence prior to study treatment must have recovered from the effects of surgery (including patient's skin having fully recovered from the surgical wound) Note: a 4-week window is required after surgery prior to starting treatment. For central nervous system (CNS) -related stereotactic biopsies, a minimum of 7 days must have elapsed prior to registration.
- Residual disease of recurrent glioblastoma is not mandated for eligibility into the study. To best assess the extent of residual disease post-operatively, a post-operative MRI scan must be performed prior to registration and is recommended to be within 96 hours post-surgery (although 24-48 hours would be optimum). Note: Patients who did have surgery with a post-operative contrast-enhanced scan falling outside the 5-week window prior to registration, must have a repeat MRI scan within 14 days prior to registration.
- Patients with up to two recurrences are allowed.
- Failure on bevacizumab (either as a monotherapy or a combination) as most recent regimen confirmed by tumor recurrence on MRI.
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- The patient must have failed no more than one regimen of bevacizumab.
- The patient must not have received bevacizumab as an upfront treatment in newly diagnosed glioblastoma.
- There must be a minimum of 14 days (i.e., an interval equal to or greater than 14 days) since last treatment with bevacizumab and registration
- History/physical examination within 14 days prior to registration
- Karnofsky performance status ≥ 70 within 14 days prior to registration
- Age ≥ 22
- Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3
- Platelets ≥ 75,000 cells/mm3
- Hemoglobin (Hgb) ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dl is acceptable.)
- Creatinine ≤ 1.5 mg/dl
- Urine protein: creatinine (UPC) ratio < 1.0 within 14 days prior to registration OR urine dipstick for proteinuria ≤ 2+ (patients discovered to have > 2+ proteinuria on dipstick urinalysis at baseline must have a UPC ratio done that is <1.0 to be eligible. If the UPC ratio is ≥ 1.0 then the patients should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
- Note: UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion; a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm. UPC ratio is calculated using one of the following formulas:
- [urine protein]/[urine creatinine]: if both protein and creatinine are reported in mg/dL
- [(urine protein) x0.088]/[urine creatinine]: if urine creatinine is reported in mmol/L
- Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) within 14 days prior to registration
- Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3.0 x ULN within 14 days prior to registration
- Patients on full dose anticoagulants (e.g., warfarin or low molecular weight (LMW) heparin) must meet both of the following criteria:
- No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices) within 14 days prior to registration
- One of the below criteria must be met based on patient's therapy:
- Warfarin: In-range international normalized ratio (INR) (usually between 2 and 3) within 14 days prior to registration
- LMW heparin or novel oral anti-coagulant: stable dose within 14 days prior to registration
- Patients must have recovered from the toxic effects of prior therapy at the time of registration as follows:
- 28 days from the administration of any investigational agent
- 28 days from administration of prior cytotoxic therapy with the following exceptions:
- 14 days from administration of vincristine or irinotecan
- 42 days from administration of nitrosoureas
- 21 days from administration of procarbazine
- 7 days from administration of non-cytotoxic agents [e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count)]
- Female patients of child-bearing potential must have a negative serum pregnancy test within 14 days prior to registration.
- Patient must be maintained on a stable or decreasing dose of corticosteroid for at least 5 days before the baseline scan.
- Minimum interval since completion of radiation treatment at the time of registration is 90 days.
- Patient must provide study specific informed consent prior to study entry.
Who cannot join
- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years. (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
- Infra-tentorial tumor.
- > 1 cm diameter of blood seen on contrast MRI (with and without gadolinium contrast)
- Major surgery such as intra-thoracic, intra-abdominal or intra-pelvic (with the exception of craniotomy), open biopsy or significant traumatic injury ≤ 4 weeks prior to registration, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device ≤ 1 week prior to registration, or who have not recovered from side effects of such procedure or injury.
- Implanted pacemaker, defibrillator or deep brain stimulator, other implanted electronic devices in the brain.
- Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months prior to registration.
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- Transmural myocardial infarction within the last 6 months prior to registration
- Cerebrovascular accident (CVA), transient ischemic attack (TIA) within the last 6 months prior to registration
- Pulmonary embolism (PE) within the last 6 months prior to registration
- Uncontrolled hypertension (defined by a systolic blood pressure (SBP) ≥ 160 mm Hg or diastolic blood pressure (DBP) ≥ 100 mm Hg while on anti-hypertensive medications) within 14 days prior to registration.
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration.
- Chronic lung disease or Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration.
- Severe hepatic disease, defined as a diagnosis of Child-Pugh Class B or C hepatic disease.
- Known HIV positive patients.
- 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.
- Skull defects such as missing bone flap, a shunt, or bullet fragments.
- Significant intracranial pressure as per treating physician that may require surgical intervention.
- Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception.
- Breast feeding women.
- Prior allergic reaction to bevacizumab or severe adverse event with bevacizumab.
- Known sensitivity to conductive hydrogels.
- Prior treatment with the Optune® system.
- Active treatment on another clinical trial.
Trial locations and contacts
11 sites in 1 country.
11 sites in 1 country
United States11 sites
Emory University
Atlanta, Georgia, 30322
Medical University of South Carolina
Charleston, South Carolina, 29425
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
University of California, San Diego
La Jolla, California, 92093
Miami Cancer Institute at Baptist Health
Miami, Florida, 33176
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
University of California Irvine, Chao Family Comprehensive Cancer Center
Orange, California, 92868
UF Health Cancer Center at Orlando Health
Orlando, Florida, 32806
Thomas Jefferson University
Philadelphia, Pennsylvania, 19107
University of Rochester
Rochester, New York, 14642
Washington University School of Medicine
St Louis, Missouri, 63100
About this study
Official title: Phase II Trial Of Optune® Plus Bevacizumab In Bevacizumab-Refractory Recurrent Glioblastoma
This phase II trial will investigate the efficacy and safety of the addition of Optune (Tumor Treating Fields [TTFields] Therapy) to bevacizumab for patients with bevacizumab-refractory recurrent glioblastoma.
Read the detailed description
Patients that have recurrent glioblastoma that has progressed on bevacizumab continue to receive bevacizumab with the addition of Tumor Treating Fields Therapy. Treatment is given until disease progression or the development of adverse events that require complete discontinuation.
- Conditions
- Glioblastoma, Glioma, Gliosarcoma
- Being tested
- Bevacizumab, TTFields Therapy
- Keywords
- Glioblastoma, Glioma, Gliosarcoma, Optune, TTFields
- Medical subject headings
- Glioblastoma, Glioma, Gliosarcoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BevacizumabDrug
Also called Avastin
10 mg/kg every 2 weeks intravenously over 30 minutes.
TTFields TherapyDevice
Also called Optune, Tumor Treating Fields Therapy, TTF Therapy
Device is worn continuously at least 18 hours a day on average, with 1-3 days off every four weeks.
| Study group | Role | What they receive |
|---|---|---|
| Bevacizumab and TTFields Therapy | Experimental | Bevacizumab starts on the first day (+/- 1 day) of Tumor Treating Fields (TTFields) therapy. Treatment is given until disease progression or the development of adverse events that require complete discontinuation. Receives: Drug: Bevacizumab; Device: TTFields Therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Survival at 6 Months
Number of participants alive at 6 months. Out of the planned 80 eligible patients, if 36 or more were alive at six months then the null hypothesis that the six-month survival rate is 35% or less would be rejected, concluding that the six-month survival is at least 35%. No testing was done due to the small number of participants resulting from early study closure.
Measured: From registration to six months
Secondary outcomes (4)
Overall Survival (OS)
Survival time is defined as time from registration the to date of death from any cause or last known follow-up (censored) and was to be estimated by the Kaplan-Meier method. Given the small number of participants due to early study closure, only the number of patients last reported to be alive at time of study termination is reported.
Measured: From registration to study termination. Maximum follow-up was 21.8 months.
Progression-Free Survival
Progression is defined by the Modified Response Assessment in Neuro-Oncology (RANO) Response Criteria. (The precise definition is too long to be included here.) Progression-free survival time is defined as time from registration to the date of first progression, death, or last known follow-up. Progression-free survival rates were to be estimated using the Kaplan-Meier method. Given the small number of participants due to early study closure, only the number of patients last reported to be alive without progression at time of study termination is reported.
Measured: From registration to study termination. Maximum follow-up was 21.8 months.
Number of Participants With Partial or Complete Response
Modified Response Assessment in Neuro-Oncology (RANO) Response Criteria was used to define response and progression. (The precise definitions are too long to be included here.) Objective response is defined as complete or partial response. The percentage of participants with objective response was to be estimated using the exact binomial method with accompanying 95% confidence intervals. Given the small number of participants due to early study closure, only the number of patients with objective response is reported.
Measured: From registration to study termination. Maximum follow-up was 21.8 months.
Number of Participants With Grade 3+ Treatment-related Adverse Events
Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the adverse event (AE). The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. The percentage of participants with grade 3 or higher treatment-related adverse events was to be estimated using the exact binomial method with accompanying 95% confidence intervals.
Measured: From registration to study termination. Maximum follow-up was 21.8 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Apr 2016 (estimated)
- Study start9 May 2017
- Primary completion15 Oct 2019
- Study completion15 Oct 2019
Why it stopped: Treatment now available commercially
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for GlioblastomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- RTOG Foundation, Inc.
- Sponsor type
- University, hospital or other
- Collaborators
- NovoCure Ltd.
- Responsible party
- Sponsor
- Investigators
- Manmeet Ahluwalia, MD, FACP, Principal investigator, RTOG Foundation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02743078
- Sponsor's protocol ID
- RTOG 3503
- Other IDs
- RF 3503
- Status last verified
- Oct 2020
- First submitted
- 5 Apr 2016
- Last updated
- 2 Jun 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 2 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Trial Of Optune® Plus Bevacizumab In Bevacizumab-Refractory Recurrent Glioblastoma
- ClinicalTrials.gov ID
- NCT02743078
- Acronym / sponsor ID
- RTOG 3503
- Conditions
- Glioblastoma, Glioma, Gliosarcoma
- Keywords
- Glioblastoma, Glioma, Gliosarcoma, Optune, TTFields
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Treatment now available commercially
- Enrolment
- 3 participants (actual)
- Lead sponsor
- RTOG Foundation, Inc.University, hospital or other
- Collaborators
- NovoCure Ltd.
- Study start
- 9 May 2017 (actual)
- Primary completion
- 15 Oct 2019 (actual)
- Study completion
- 15 Oct 2019 (actual)
- First posted
- 19 Apr 2016 (estimated)
- Results
- Posted 17 Nov 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase II trial will investigate the efficacy and safety of the addition of Optune (Tumor Treating Fields [TTFields] Therapy) to bevacizumab for patients with bevacizumab-refractory recurrent glioblastoma.
Detailed description
Patients that have recurrent glioblastoma that has progressed on bevacizumab continue to receive bevacizumab with the addition of Tumor Treating Fields Therapy. Treatment is given until disease progression or the development of adverse events that require complete discontinuation.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Bevacizumab and TTFields Therapy | Experimental | Drug: Bevacizumab, Device: TTFields TherapyBevacizumab starts on the first day (+/- 1 day) of Tumor Treating Fields (TTFields) therapy. Treatment is given until disease progression or the development of adverse events that require complete discontinuation. |
Who may qualify
- Ages
- 22 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (38 listed)
- Histologically proven diagnosis of glioblastoma or other grade IV malignant glioma (including variants of glioblastoma i.e., gliosarcoma, giant cell glioblastoma, etc.).
- Confirmation of tumor recurrence or progression on contrast magnetic resonance imaging (MRI) (with and without gadolinium contrast) as determined by Response assessment in neuro-oncology (RANO) criteria within 14 days prior to registration for patients who did not have recent resection of their glioblastoma or only had a stereotactic biopsy.
- Patients having undergone recent resection (within 5 weeks prior to registration) of their glioblastoma to treat current recurrence prior to study treatment must have recovered from the effects of surgery (including patient's skin having fully recovered from the surgical wound) Note: a 4-week window is required after surgery prior to starting treatment. For central nervous system (CNS) -related stereotactic biopsies, a minimum of 7 days must have elapsed prior to registration.
- Residual disease of recurrent glioblastoma is not mandated for eligibility into the study. To best assess the extent of residual disease post-operatively, a post-operative MRI scan must be performed prior to registration and is recommended to be within 96 hours post-surgery (although 24-48 hours would be optimum). Note: Patients who did have surgery with a post-operative contrast-enhanced scan falling outside the 5-week window prior to registration, must have a repeat MRI scan within 14 days prior to registration.
- Patients with up to two recurrences are allowed.
Key exclusion criteria (23 listed)
- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years. (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
- Infra-tentorial tumor.
- > 1 cm diameter of blood seen on contrast MRI (with and without gadolinium contrast)
- Major surgery such as intra-thoracic, intra-abdominal or intra-pelvic (with the exception of craniotomy), open biopsy or significant traumatic injury ≤ 4 weeks prior to registration, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device ≤ 1 week prior to registration, or who have not recovered from side effects of such procedure or injury.
- Implanted pacemaker, defibrillator or deep brain stimulator, other implanted electronic devices in the brain.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BevacizumabAlso: Avastin10 mg/kg every 2 weeks intravenously over 30 minutes. | Drug | Bevacizumab and TTFields Therapy |
| TTFields TherapyAlso: Optune, Tumor Treating Fields Therapy, TTF TherapyDevice is worn continuously at least 18 hours a day on average, with 1-3 days off every four weeks. | Device | Bevacizumab and TTFields Therapy |
Primary outcome
Overall Survival at 6 Months
Time frame: From registration to six months
Number of participants alive at 6 months. Out of the planned 80 eligible patients, if 36 or more were alive at six months then the null hypothesis that the six-month survival rate is 35% or less would be rejected, concluding that the six-month survival is at least 35%. No testing was done due to the small number of participants resulting from early study closure.
4 secondary outcomes
Overall Survival (OS)
Time frame: From registration to study termination. Maximum follow-up was 21.8 months.
Progression-Free Survival
Time frame: From registration to study termination. Maximum follow-up was 21.8 months.
Number of Participants With Partial or Complete Response
Time frame: From registration to study termination. Maximum follow-up was 21.8 months.
Number of Participants With Grade 3+ Treatment-related Adverse Events
Time frame: From registration to study termination. Maximum follow-up was 21.8 months.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jun 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Manmeet Ahluwalia, MD, FACP principal investigator
RTOG Foundation
11 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Bevacizumab and TTFields Therapy in people with Glioblastoma and Glioma, run by RTOG Foundation, Inc. at 11 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 38 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 2 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 11 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Nov 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall Survival at 6 Months (time frame: From registration to six months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jun 2021.