Optune® Plus Bevacizumab in Bevacizumab-Refractory Recurrent Glioblastoma
Condition: Glioblastoma; Glioma; Gliosarcoma
MeSH terms: Glioblastoma; Gliosarcoma
Intervention: Bevacizumab; TTFields Therapy
Intervention description: 10 mg/kg every 2 weeks intravenously over 30 minutes.; Device is worn continuously at least 18 hours a day on average, with 1-3 days off every four weeks.
Intervention MeSH terms: Bevacizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 22 Years
Healthy volunteers: No
Keywords: Glioblastoma; Glioma; Gliosarcoma; Optune; TTFields

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.
    

Eligibility criteria:

        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 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.

               -  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:

               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 international normalized ratio (INR) (usually between 2
                       and 3) within 14 days prior to registration

                    2. 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.

        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 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.