Pembrolizumab and Reirradiation in Bevacizumab Naïve and Bevacizumab Resistant Recurrent Glioblastoma
Condition: Glioblastoma
MeSH terms: Glioblastoma
Intervention: Pembrolizumab; Bevacizumab; Re-irradiation
Intervention description: Pembrolizumab is a drug (an antibody) that may treat cancer by working with the immune system; Bevacizumab (also known as "Avastin") is designed to prevent or slow down the growth of cancer cells by blocking the growth of blood vessels.; Radiotherapy destroys cancer cells using radiation aimed at a cancer from a machine
Intervention MeSH terms: Bevacizumab; Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 60.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Glioblastoma

Summary:

      This research study is studying pembrolizumab and re-irradiation as possible treatments for
      glioblastoma.

      The drugs involved in this study are:

        -  Pembrolizumab

        -  Radiation

        -  Bevacizumab, an FDA-approved drug for treating recurrent glioblastoma multiforme (GBM)
    

Eligibility criteria:

        INCLUSION CRITERIA:

        1.1 Histologically confirmed World Health Organization (WHO) Grade IV glioblastoma.
        Patients with original histology of low-grade glioma and subsequent histological diagnosis
        of GBM are eligible. Other WHO grade IV glial neoplasms such as gliosarcoma are NOT
        eligible 1.2 Willing and able to provide written informed consent/assent for the trial 1.3
        ≥ 18 years of age on day of signing informed consent 1.4 Karnofsky performance status (KPS)
        ≥ 70 (Appendix A) 1.5 Unequivocal evidence for tumor progression by MRI scan 1.6 MRI within
        14 days prior to start of study therapy (with vascular imaging when possible).
        Corticosteroid dose must be stable or decreasing for at least 5 days prior to the scan. If
        steroids are added or the steroid dose is increased between the date of the screening MRI
        scan and Day 1 dose, a new baseline scan is required 1.7 Measurable disease as per Response
        Assessment in Neuro-Oncology (RANO) criteria 1.8 Cohort A patients must be at their first
        or second relapse; Cohort B patients must have progressed on no more than one prior
        bevacizumab-containing regimen (may have received any # of non-bevacizumab-containing
        regimens). Patients who were treated with prior bevacizumab but did not progress or
        experienced significant toxicity, are not eligible 1.9 Previous first line therapy with at
        least radiotherapy utilizing standard dosing of CNS radiation - for either high-grade or
        low-grade glial neoplasm 1.10 The following time periods must have elapsed from projected
        Day 1 dose:

          1. At least 3 weeks from prior surgical resection

          2. At least 1 week from stereotactic biopsy

          3. At least 6 months from completion of prior radiotherapy (patient may still be eligible
             if s/he has a new area of enhancement outside the 80% isodose line of the original
             radiation field)

          4. At least 4 weeks from cytotoxic therapy (at least 23 days for temozolomide, and at
             least 6 weeks from nitrosoureas)

          5. At least 1 week from cancer vaccines

          6. At least 6 weeks from antibodies

          7. At least 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor
             therapies (not including tumor treating fields or cancer vaccines); at least 1 week
             from NovoTTF (Optune) or other tumor treating fields and cancer vaccines

          8. Cohort B patients only: Day 1 of bevacizumab on-study must be at least 3 weeks from
             last dose of prior course of Avastin/bevacizumab.

        1.11 All clinically significant toxic effects of prior therapy must have recovered to grade
        0 or 1 or pre-treatment baseline (excluding alopecia, laboratory values listed per
        inclusion criteria, and lymphopenia) 1.12 Adequate organ function as defined below
        (screening labs performed within 14 days of treatment initiation): 1.12.1 Hematologic:
        Absolute neutrophil count (ANC) ≥1,500 /uL; Platelets ≥100,000 / uL; Hemoglobin ≥9 g/dL or
        ≥5.6 mmol/L 1.12.2 Renal: Serum creatinine ≤1.5 X institutional upper limit of normal (ULN)
        OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine
        or CrCl) ≥60 mL/min for participant with creatinine levels > 1.5 X institutional ULN 1.12.3
        Hepatic Serum total bilirubin ≤ 1.5 X institutional ULN OR Direct bilirubin ≤ institutional
        ULN for participants with total bilirubin levels > 1.5 X institutional ULN; aspartate
        aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; SGPT) ≤ 2.5 X institutional
        ULN (OR ≤ 5 X institutional ULN for participants with Gilberts syndrome) 1.12.4
        Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) Activated
        Partial Thromboplastin Time (aPTT) ≤1.5 X institutional ULN unless participant is receiving
        anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of
        anticoagulants 1.12.5 Pulmonary: Resting baseline oxygen saturation by pulse oximetry ≥92%
        at rest

        1.13 Negative urine or serum pregnancy within 72 hours prior to registration from any woman
        of child-bearing potential (WOCBP), defined as any woman physiologically capable of
        becoming pregnant. If the urine test is positive or cannot be confirmed as negative, a
        serum pregnancy test will be required.

        1.14 WOCBP (defined above) must agree to use a highly effective method of contraception
        (detailed in protocol eligibility) consistently and correctly as described below during
        study treatment and for 120 days after study discontinuation.

        1.15 Male participants must agree to use at least one of the methods of contraception
        detailed in protocol eligibility starting with the first dose of study therapy through 120
        days after the last dose of therapy.

        EXCLUSION CRITERIA:

        2.1 Recurrent tumor greater than 6 cm in maximum diameter 2.2 Currently participating or
        plans to participate in another study of an investigational agent or using an
        investigational device.

        2.3 Tumor primarily localized to the brainstem or spinal cord. 2.4 Presence of multifocal
        tumor, diffuse leptomeningeal or extracranial disease.

        NOTE: Not all instances of multifocal disease will exclude a potential patient; only
        patients with multifocal sites of active disease will be excluded. (e.g. A patient with a
        previously treated lesion that remains stable would not be excluded.)

        Medical History/Conditions/Concomitant Medical Illnesses:

        2.5 Diagnosis of immunodeficiency. 2.6 History or current evidence of any condition,
        therapy, or laboratory abnormality that might confound the results of the trial, interfere
        with the participant's participation for the full duration of the trial, or is not in the
        best interest of the participant to participate, in the opinion of the treating
        investigator. e.g. unstable angina pectoris, cardiac arrhythmia or psychiatric
        illness/social situations that would limit compliance with study requirements.

        2.7 History of known coagulopathy that increases risk of bleeding or a history of
        clinically significant hemorrhage within 12 months of start of study drug.

        2.8 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.

        2.9 Gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3 within
        6 months of start of study drug.

        2.10 Known additional malignancy that is progressing or requires active treatment within 1
        year of start of study drug, except for those treated with surgical therapy only (e.g.
        basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical
        cancer that has undergone potentially curative therapy).

        2.11 Active autoimmune disease requiring systemic treatment in the past 2 years (e.g. with
        use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement
        therapy (eg thyroxine, insulin, or physiologic corticosteroid replacement for adrenal
        insufficiency or pituitary/hypothalamic dysfunction, etc.) is not considered a form of
        systemic treatment.

        2.12 History of (non-infectious) pneumonitis that required steroids or has current
        pneumonitis.

        2.13 Active infection requiring systemic therapy. 2.14 Known psychiatric or substance abuse
        disorders that would interfere with cooperation with the requirements of the trial.

        2.15 Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) and is
        receiving antiretroviral therapy.

        2.16 Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C [e.g., hepatitis C
        virus (HCV) RNA (qualitative) is detected].

        2.17 History of non-healing wounds or ulcers, or bone refractures within 3 months of
        fracture.

        2.18 History of arterial thromboembolism within 12 months of start of study drug.

        2.19 Clinically significant cardiovascular disease within 12 months of start of study drug,
        including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular
        disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or
        arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary
        angioplasty/stent.

        2.20 Known history of active Bacillus Tuberculosis (TB) 2.21 Known hypersensitivity to any
        of the study therapy products and/or any of their excipients.

        2.22 Is pregnant or breastfeeding, or expecting to conceive within the projected duration
        of the trial, starting with the screening visit through 120 days after the last dose of
        trial treatment.

        Prior Therapy:

        2.23 Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic
        radiosurgery or therapeutics delivered by local injection or convection enhanced delivery
        (this exclusion applies to any locally administered therapy, including intratumoral
        vaccines).

        2.24 Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 or with an
        agent directed to another stimulatory or co-stimulatory T-cell receptor (eg CTLA-4, OX-40,
        CD137). (These therapies target checkpoint proteins on immune cells called T-Cells.PD-1 =
        Programmed cell death protein 1. CTLA-4 = cytotoxic T-lymphocyte-associated protein 4.
        OX-40 - AKA CD134 & TNFRSF4 = Tumor necrosis factor receptor superfamily, member 4) 2.25
        Has received prior Vascular endothelial growth factor (VEGF) or VEGFR inhibitor therapy
        such as bevacizumab, cediranib, aflibercept, vandetanib, XL-184 (Cabozantinib), sunitinib,
        etc. (Cohort A only)

        Other Meds:

        2.26 Is receiving any form of immunosuppressive therapy (e.g. chronic systemic steroid
        therapy exceeding dosage of 10 mg daily of prednisone equivalent) within 7 days prior to
        the first dose of study drug.

        2.27 Has received systemic immunosuppressive treatments (aside from systemic
        corticosteroids as described in protocol) within six months of start of study drug (such as
        methotrexate, chloroquine, azathioprine, etc).

        2.28 Requires treatment with high dose systemic corticosteroids defined as dexamethasone >
        2 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of start of study
        drug.

          -  Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone
             equivalents are permitted in the absence of active autoimmune disease.

          -  Participants are permitted to use topical, ocular, intra-articular, intranasal, and
             inhalational corticosteroids (with minimal systemic absorption).

          -  Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10
             mg/day prednisone equivalents.

          -  A brief course of corticosteroids for prophylaxis or for treatment of non-autoimmune
             conditions is permitted.

        2.29 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. (Therapeutic or prophylactic therapy with low-molecular weight heparin is allowed.)
        2.30 Has received a live vaccine within 30 days prior to the first dose of study drug.