Pembrolizumab +/- Bevacizumab for Recurrent GBM
Condition: Glioblastoma
MeSH terms: Glioblastoma
Intervention: Pembrolizumab; Bevacizumab
Intervention MeSH terms: Bevacizumab; Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: There is a safety lead-in before the start of the randomized phase 2 study.
Masking: None (Open Label)
Enrollment: 80.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Recurrent

Summary:

      In this research study, the investigators are looking to determine the effectiveness of
      Pembrolizumab (MK-3475) when given with bevacizumab or when given alone for the treatment of
      recurrent glioblastoma multiforme (GBM). This study will also test the safety and
      tolerability of Pembrolizumab (MK-3475) when given alone or with bevacizumab.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Have histologically confirmed World Health Organization Grade IV malignant glioma
             (glioblastoma or gliosarcoma). Participants will be eligible if the original histology
             was low-grade glioma and a subsequent histological diagnosis of glioblastoma or
             variants is made.

          -  Previous first line therapy with at least radiotherapy and temozolomide

          -  Be at first or second relapse.

          -  Participants must have shown unequivocal evidence for tumor progression by MRI or CT
             scan.

          -  CT or MRI within 14 days prior to start of study drug.

          -  An interval of at least 4 weeks (to start of study agent) between prior surgical
             resection or one week for stereotactic biopsy.

          -  An interval of at least 12 weeks from the completion of radiation therapy to start of
             study drug unless there is a new area of enhancement consistent with recurrent tumor
             outside the radiation field or there is unequivocal histologic confirmation of tumor
             progression

          -  Participants must have recovered to grade 0 or 1 or pre-treatment baseline from
             clinically significant toxic effects of prior therapy (including but not limited to
             exceptions of alopecia, laboratory values listed per inclusion criteria, and
             lymphopenia which is common after therapy with temozolomide).

          -  From the projected start of scheduled study treatment, the following time periods must
             have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic
             therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from
             antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor
             therapies.

        Exclusion Criteria:

          -  Current or planned participation in a study of an investigational agent or using an
             investigational device.

          -  Has a diagnosis of immunodeficiency.

          -  Has tumor primarily localized to the brainstem or spinal cord.

          -  Has presence of diffuse leptomeningeal disease or extracranial disease.

          -  Has received systemic immunosuppressive treatments within 6 months of start of study
             drug

          -  Requires treatment with high dose systemic corticosteroids defined as dexamethasone >
             4 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of start of
             study drug.

          -  Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic
             radiosurgery or therapeutics delivered by local injection or convection enhanced
             delivery.

          -  Requires therapeutic anticoagulation with warfarin at baseline; patients must be off
             warfarin or warfarin-derivative anti-coagulants for at least 7 days prior to starting
             study drug; however, therapeutic or prophylactic therapy with low-molecular weight
             heparin is allowed.

          -  Has history of known coagulopathy that increases risk of bleeding or a history of
             clinically significant hemorrhage within 12 months of start of study drug

          -  Has evidence of intratumoral or peritumoral hemorrhage on baseline MRI scan other than
             those that are grade ≤ 1 and either post-operative or stable on at least 2 consecutive
             MRI scans.

          -  Has gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3
             within 6 months of start of study drug.

          -  Has a known additional malignancy that is progressing or requires active treatment
             within 3 years of start of study drug. Exceptions include basal cell carcinoma of the
             skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has
             undergone potentially curative therapy.

          -  Has an active autoimmune disease requiring systemic treatment within the past 3 months
             or a documented history of clinically severe autoimmune disease, or a syndrome that
             requires systemic steroids or immunosuppressive agents.

          -  Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

          -  Has an active infection requiring systemic therapy.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Is pregnant or breastfeeding, or expecting to conceive within the projected duration
             of the trial

          -  Has a known history of HIV

          -  Has known active Hepatitis B or Hepatitis C

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.

          -  Has a known hypersensitivity to any of the study therapy products.

          -  Has received anti-angiogenic or anti-VEGF targeted agents (e.g. bevacizumab,
             cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc)

          -  Has a history of non-healing wounds or ulcers, or bone refractures within 3 months of
             fracture

          -  Has a history of arterial thromboembolism within 12 months of start of study drug.

          -  Has inadequately controlled hypertension

          -  Has a history of hypertensive crisis or hypertensive encephalopathy

          -  Has had clinically significant cardiovascular disease within 12 months of start of
             study drug

          -  Has a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal
             abscess within 6 months prior to start of study drug.