Nivolumab, Ipilimumab, and Short-course Radiotherapy in Adults With Newly Diagnosed, MGMT Unmethylated Glioblastoma
Condition: MGMT-unmethylated Glioblastoma (GBM); GBM
MeSH terms: Glioblastoma
Intervention: Nivolumab; Ipilimumab; Radiation Therapy (RT)
Intervention description: study treatment on Day 1 with one dose of nivolumab 3 mg/kg; study treatment on Day 1 with one dose of ipilimumab 1mg/kg; total dose of 30 Gy, given in 5 consecutive fractions of 6 Gy each fraction.
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No

Summary:

      This is a single arm, open-label, phase II trial of nivolumab, ipilimumab and short-course
      radiation therapy in adult patients with newly diagnosed, MGMT unmethylated GBM with the
      primary objective of determining the overall survival at 1 year.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female subjects aged ≥18 years.

          -  Histopathological evidence of glioblastoma or gliosarcoma, WHO grade IV.

          -  Tumor MGMT promoter DNA not methylated (i.e., unmethylated) by central testing.

          -  Maximal tumor diameter (including residual tumor and resection cavity if subjects had
             tumor resection rather than only stereotactic biopsy) of 6.6 cm or less. Maximal tumor
             size allowed is derived from an estimated maximal radiotherapy planning target volume
             (PTV) of 150 cm3.

          -  Subjects must not have received any prior standard or investigational anti-tumor
             therapy other than surgery and must not intend to receive any standard or
             investigational anti-tumor therapy other than the study regimen.

          -  Karnofsky performance status (Appendix 2) of ≥60.

          -  Availability of a paraffin-embedded or frozen tumor-tissue block with a minimum of 1
             cm2 of tumor surface area, or 20 unstained slides from the glioblastoma tissue
             specimen if a tumor block cannot be submitted.

          -  Subjects must start study agent within 6 weeks from the first diagnostic surgery for
             glioblastoma.

          -  An interval of at least 2 weeks for surgical resection and 1 week for stereotactic
             biopsy from the start of study treatment.

          -  A contrast-enhanced MRI must be obtained within 7 days of the first dose of study
             treatment.

          -  Adequate hematologic, hepatic, and renal function defined by

               -  White blood cell count ≥ 2.0 x 109/L

               -  Absolute neutrophil count ≥ 1.5 x 109/L

               -  Platelet count ≥ 100 x 109/L

               -  Hemoglobin > 9 g/dL

               -  Serum creatinine ≤1.5 x upper limit of normal (ULN) or creatinine clearance
                  (CrCl) ≥ 40 mL/min according to the Cockcroft-Gault formula or local
                  institutional standard method

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN

               -  Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
                  total bilirubin < 3.0 mg/dL)

          -  Women of child-bearing potential (WOCBP) and men able to father a child must agree to
             use highly effective contraception (any contraceptive method with a failure rate of
             less than 1% per year) while on study drug and for 23 weeks (for women) or 31 weeks
             (for men) after the last dose of study drug.

               1. WOCBP must have a negative serum or urine pregnancy test within 24 hours of
                  initiation of study drug.

               2. WOCBP is defined as any female who has experienced menarche and who has not
                  undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who
                  is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea
                  in a woman over 45 in the absence of other biological or physiological causes. In
                  addition, women under the age of 55 must have a documented serum follicle
                  stimulating hormone (FSH) level less than 40 mIU/mL to be defined as
                  post-menopausal.

               3. WOCBP receiving nivolumab will be instructed to adhere to contraception for a
                  period of 23 weeks after the last dose of investigational product. Men receiving
                  nivolumab and who are sexually active with WOCBP will be instructed to adhere to
                  contraception for a period of 31 weeks after the last dose of investigational
                  product. These durations have been calculated using the upper limit of the
                  half-life for nivolumab (25 days) and are based on the protocol requirement that
                  WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually
                  active with WOCBP use contraception for 5 half-lives plus 90 days.

               4. Highly effective contraceptive measures include: stable use of oral
                  contraceptives such as combined estrogen and progestogen and progestogen only
                  hormonal contraception or other prescription pharmaceutical contraceptives for 2
                  or more menstrual cycles prior to screening; intrauterine device [IUD];
                  intrauterine hormone-releasing system (IUS); bilateral tubal ligation; vasectomy
                  and sexual abstinence.

               5. Contraception is not required for men with documented vasectomy.

               6. Pregnancy testing and contraception are not required for women with documented
                  hysterectomy or tubal ligation.

               7. Women must not be breastfeeding.

          -  Willing to and capable of providing written informed consent prior to any study
             related procedures.

          -  Ability and willingness to comply with all study requirements, including scheduled
             visits, treatment plans, laboratory tests, and other study-related procedures.

        Exclusion Criteria:

          -  Prior use of any standard or investigational anti-tumor therapy other than surgery

          -  Planned participation in another study of an investigational agent or investigational
             device or planned use of any other agent or therapeutic device intended for therapy of
             glioma.

          -  Prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4
             antibody, or any other antibody or drug specifically targeting T-cell costimulation or
             immune checkpoint pathways.

          -  Primary brainstem or spinal cord tumor.

          -  Diffuse leptomeningeal gliomatosis.

          -  Known mutation of the IDH1 or IDH2 genes in the tumor, since glioblastomas with these
             mutations have different biology and are associated with improved prognosis.

          -  Systemic treatment with either immunosuppressive doses of corticosteroids (> 10 mg
             daily prednisone equivalents) or other immunosuppressive medications within 14 days of
             study drug administration.

               1. Subjects on a standard high-dose steroid taper after craniotomy or stereotactic
                  biopsy may have received a higher dose of corticosteroids within 14 days of
                  registration, however must be at a dose < 10 mg daily prednisone or bioequivalent
                  per day within 5 days prior to initiation of study drug.

               2. Administration of steroids through a route known to result in a minimal systemic
                  exposure [i.e., intranasal, intraocular, inhaled, topical, or local injection
                  (e.g., intra-articular injection) corticosteroids (<5% of body surface area)] are
                  permitted in the absence of active autoimmune disease.

               3. Subjects requiring adrenal replacement with corticosteroids are eligible if the
                  steroids are at doses ≤ 10 mg prednisone or bioequivalent per day in the absence
                  of active autoimmune disease.

               4. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication) are allowed.

          -  Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory
             agent. The following conditions are not exclusions (subjects with the following
             conditions are permitted):

             a.Patients with diabetes type I, vitiligo, residual hypo- or hyperthyroidism due to
             autoimmune condition only requiring hormone replacement, or psoriasis not requiring
             systemic immunosuppressive treatment, or autoimmune conditions not expected to recur
             in the absence of an external trigger.

          -  Prior organ transplantation, including allogeneic stem cell transplantation.

          -  Known history of, or any evidence of active, non-infectious pneumonitis within the
             last 5 years.

          -  Known severe (NCI-CTCAE v4.03 Grade 3 or 4) infusion-related allergy or acute
             hypersensitivity reaction attributed to any monoclonal antibody, any history of
             anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially
             controlled asthma).

          -  Unable tolerate an MRI, or have a contraindication to MRI.

          -  Active infection requiring systemic therapy.

          -  Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome.

          -  Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
             (HCV antibody) indicating acute or chronic infection.

          -  Vaccination within 4 weeks of the first dose of study drug and while on trials is
             prohibited except for administration of inactivated vaccines. Note: Seasonal influenza
             vaccines for injection are generally inactivated flu vaccines and are allowed; however
             intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are
             not allowed.

          -  Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
             accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
             prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart
             Association Classification Class II), or serious cardiac arrhythmia requiring
             medication.

          -  Patients with another active cancer [excluding basal cell carcinoma, cervical
             carcinoma in situ or melanoma in situ]. Prior history of other cancer is allowed, as
             long as there was no active disease within the prior 2 years.

          -  All other unstable, severe, or chronic medical or psychiatric conditions including
             colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis, recent (within
             the past year) or active suicidal ideation or behavior, known alcohol or drug abuse,
             or laboratory abnormalities that may increase the risk associated with study
             participation or study treatment administration or may interfere with the
             interpretation of study results and, in the judgment of the investigator, would make
             the patient inappropriate for entry into this study.