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Optune® Plus Bevacizumab in Bevacizumab-Refractory Recurrent Glioblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02743078
Recruitment Status : Terminated (Treatment now available commercially)
First Posted : April 19, 2016
Last Update Posted : November 1, 2019
Sponsor:
Collaborator:
NovoCure Ltd.
Information provided by (Responsible Party):
RTOG Foundation, Inc.

Tracking Information
First Submitted Date  ICMJE April 5, 2016
First Posted Date  ICMJE April 19, 2016
Last Update Posted Date November 1, 2019
Actual Study Start Date  ICMJE April 12, 2017
Actual Primary Completion Date October 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 14, 2016)
Overall Survival (OS) at 6 months [ Time Frame: From the date of registration to 6 months after the date of registration ]
Overall Survival rate at 6 months after the date of registration
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 14, 2016)
  • Overall Survival (OS) [ Time Frame: From the date of registration to the date of death or last follow-up (last date on which the patient was reported alive). OS will be assessed through study completion, an average of 2 years. ]
    Overall Survival (OS)
  • Progression-Free Survival (PFS) [ Time Frame: From the date of registration to the date of first progression or death or last follow-up (last date on which the patient was reported alive without progression). PFS will be assessed through study completion, an average of 2 years. ]
    Progression-Free Survival (PFS)
  • Objective Response Rate (ORR) [ Time Frame: Best response recorded from the start of treatment until disease progression. ORR will be assessed through study completion, an average of 2 years. ]
    Objective Response Rate
  • Frequencies of Treatment-Related Adverse Events [ Time Frame: Adverse events will be assessed from the start of treatment through study completion, an average of 2 years. ]
    Combined adverse events from the treatment period and follow-up period.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Optune® Plus Bevacizumab in Bevacizumab-Refractory Recurrent Glioblastoma
Official Title  ICMJE Phase II Trial Of Optune® Plus Bevacizumab In Bevacizumab-Refractory Recurrent Glioblastoma
Brief Summary This phase II trial will investigate the efficacy and safety of the addition of Optune (Tumor Treating Fields or TTF 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma
  • Glioma
  • Gliosarcoma
Intervention  ICMJE
  • Drug: Bevacizumab
    Vascular endothelial growth factor A (VEGF-A) angiogenesis inhibitor
    Other Name: Avastin
  • Device: TTFields
    Tumor treating low intensity, intermediate frequency electric fields
    Other Name: Optune
Study Arms  ICMJE Experimental: Arm I (Bevacizumab and TTFields)
Patients will receive bevacizumab at a dose of 10 mg/kg every 2 weeks on a 4-week cycle and TTFields continuously. Treatment is given until disease progression or the development of adverse events that require complete discontinuation. Bevacizumab starts on the first day (+/- 1 day) of TTFields therapy.
Interventions:
  • Drug: Bevacizumab
  • Device: TTFields
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: February 11, 2019)
3
Original Estimated Enrollment  ICMJE
 (submitted: April 14, 2016)
85
Actual Study Completion Date  ICMJE October 15, 2019
Actual Primary Completion Date October 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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 MRI (with and without gadolinium contrast) as determined by 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 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.

    • 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 ≥ 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
  • ALT and AST ≤ 3.0 x ULN within 14 days prior to registration
  • Patients on full dose anticoagulants (e.g., warfarin or LMW heparin) must meet both of the following criteria:

    1. 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
    2. One of the below criteria must be met based on patient's therapy:

      1. Warfarin: In-range INR (usually between 2 and 3) within 14 days prior to registration
      2. Low molecular weight 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.

Exclusion Criteria:

  • 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.
  • 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 SBP ≥ 160 mm Hg or 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 22 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02743078
Other Study ID Numbers  ICMJE RTOG 3503
RF 3503 ( Other Identifier: RTOG Foundation )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party RTOG Foundation, Inc.
Study Sponsor  ICMJE RTOG Foundation, Inc.
Collaborators  ICMJE NovoCure Ltd.
Investigators  ICMJE
Principal Investigator: Manmeet Ahluwalia, MD, FACP RTOG Foundation
PRS Account RTOG Foundation, Inc.
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP