Clinical Trial 21681

• Overview

  Study Title:

  A Safety Run-In and Phase II Study Evaluating the Efficacy, Safety, and Impact on the Tumor Microenvironment of the Combination of Tocilizumab, Atezolizumab, and Fractionated Stereotactic Radiotherapy in Recurrent Glioblastoma

  Objective:

  Primary Objective: * Safety Run-In: To determine the maximum-tolerated dose (MTD) among three sequential dose levels: single-agent tocilizumab 4mg/kg, single-agent tocilizumab 8mg/kg, and tocilizumab 8mg/kg + atezolizumab 1680mg (each administered with FSRT), to be used for subsequent phase II testing * Phase II (non-surgical cohort): To determine the efficacy of the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT in recurrent GBM, as measured by the objective radiographic response rate (ORR) Secondary Objectives: * To estimate the progression-free survival (PFS) in patients with recurrent GBM treated with the combination of tocilizumab (anti-IL6R) and FSRT (and atezolizumab (anti-PD-L1), if Dose Level 3 is MTD) (phase II non-surgical cohort and safety run-in cohort) * To estimate the overall survival (OS) in patients with recurrent GBM treated with the combination of tocilizumab (anti-IL6R) and FSRT (and atezolizumab (anti-PD-L1), if Dose Level 3 if the MTD) (phase II non-surgical cohort and safety run-in cohort) * To estimate the progression-free survival (PFS) in patients with recurrent GBM treated with the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT (phase II surgical cohort) * To estimate the overall survival (OS) in patients with recurrent GBM treated with the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT (phase II surgical cohort) * To determine the rate and severity of AEs of the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT in recurrent glioblastoma according to CTCAE v 5.0 (separately in the nonsurgical and surgical cohorts)

• Treatments

  Therapies:

  Immunotherapy; Radiotherapy

  Medications:

  Atezolizumab (Tecentriq); Radiotherapy (); Tocilizumab ()

• Inclusion Criteria

  Inclusion Criteria:
  • Histopathologically proven diagnosis of glioblastoma, OR molecular diagnosis of glioblastoma per Consortium to Inform Molecular and Practical Approaches to Central Nervous System Tumor Taxonomy (c-IMPACT-NOW) criteria ("diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, World Health Organization [WHO] grade IV"; this requires presence of amplification of EGFR, whole chromosome 7 gain AND whole chromosome 10 loss, or TERT promoter mutation)
  • Tumor that is in first recurrence following prior first-line radiation therapy (prior dose >= 40 Gy). Prior temozolomide, prior tumor-treating fields, and/or Gliadel wafers (if placed at initial tumor resection) are allowed, but none of these are required
  • Unequivocal radiographic evidence of tumor progression by contrast-enhanced magnetic resonance imaging (MRI) scan within 21 days prior to registration
  • Per radiation oncologist review of MRI within 21 days prior to registration, must have focus of progressive, contrast-enhancing tumor that is amenable to FSRT, defined as the following: At least 1 cm x 1 cm contrast-enhancing tumor that is no greater than 4 cm in largest dimension, FSRT target is at least 0.5 cm from the optic chiasm and brainstem, Of note, multifocal disease (i.e., other sites of tumor beyond the tumor being targeted for FSRT) is allowed if the above criteria are met for the tumor that is the proposed target for FSRT.
  • Surgical cohort only (Phase II only): Must be a candidate for repeat surgery (significant debulking or gross total resection of the contrast enhancing area) as determined by the neurosurgeon or multidisciplinary team
  • Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation status must be available from any prior GBM tumor specimen; results of routinely used methods for MGMT methylation testing (e.g. mutagenically separated polymerase chain reaction [MSPCR] or quantitative polymerase chain reaction [PCR]) are acceptable)
  • The following intervals from previous treatments to registration are required to be eligible: (a) If prior radiation was = 60 Gy, an interval of least 6 months (182 days) must have elapsed since the completion of radiation therapy, unless the target lesion for FSRT is outside of the 80% isodose line of the original radiation plan (c) At least 21 days from temozolomide (d) At least 28 days from any investigational (not Food and Drug Administration [FDA]-approved for glioblastoma) agents, or within a time interval less than at least 5 half-lives of the investigational agent whichever is shorter (Note: anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapeutic antibody or pathway-targeting agents are not allowed)
  • 18 years of age or older
  • Karnofsky performance status >= 70 within 14 days prior to registration
  • History/physical examination within 14 days prior to registration
  • Adequate organ and bone marrow function per laboratory values defined in protocol.
  • Women of child-bearing potential (WOCBP)and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of receipt of study treatment, and for 60 days (males) or 90 days (females) from the last dose of tocilizumab and for 5 months (150 days) after the last dose of atezolizumab. Administration of atezolizumab or tocilizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • WOCBP must have a negative serum or urine pregnancy test within 14 days prior to registration Other criteria apply

• Exclusion Criteria

  Exclusion Criteria:
  • Known somatic tumor mutation in IDH1 or IDH2 gene. If not previously completed, sequencing of the IDH1 and IDH2 genes is not required to determine trial eligibility
  • Known germline DNA repair defect (mismatch repair deficiency, POLE mutation, e.g.). If not previously completed, germline sequencing is not required to determine trial eligibility
  • Diffuse leptomeningeal disease
  • Known contrast-enhancing tumor in brainstem or spinal cord. If not previously completed, spinal imaging is not required to determine trial eligibility
  • Patients with clinically significant mass effect or midline shift (e.g., 1-2 cm of midline shift)
  • Prior bevacizumab therapy
  • Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are excluded from this trial. Otherwise, patients with prior or concurrent malignancy are eligible
  • Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
  • Prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapeutic antibody or pathway-targeting agents
  • Treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 4 weeks prior to registration
  • Treatment with systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to registration
  • Systemic corticosteroids used to treat brain edema and/or related symptoms at a dose of > 2 mg of dexamethasone (or equivalent) daily within 5 days prior to registration. Patients receiving systemic corticosteroids for other indications are excluded
  • Patients with increased risk for gastrointestinal perforations including history of diverticulitis
  • Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
  • History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. Note: patients with the below conditions are eligible: Autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible. Controlled type 1 diabetes mellitus on a stable insulin regimen are eligible. Eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only permitted provided that they meet conditions noted in protocol.
  • History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), or organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.). History of radiation pneumonitis in a prior radiation field (fibrosis) is permitted
  • Patients with active tuberculosis (TB) are excluded
  • Severe infections within 3 weeks prior to registration including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Signs or symptoms of infection within 1 week prior to registration
  • Received oral or intravenous (IV) antibiotics within 2 weeks prior to registration. Other criteria apply

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