Phase I/II Study to Evaluate the Safety and Clinical Efficacy of Atezolizumab (aPDL1) in Combination with Temozolomide and Radiation in Patients with Newly Diagnosed Glioblastoma (GBM)
There are 2 parts to this study: Part I and Part II. The goal of Part I of this clinical research study is to study the safety and tolerability of atezolizumab in combination with radiation therapy and temozolomide. The goal of Part II of this study is to learn if atezolizumab combined with radiation therapy and temozolomide can help to control glioblastoma. The safety of this combination will also be studied.
Disease Group: Malignant neoplasms of eye brain and other parts of central nervous system
Treatment Agent: Atezolizumab,Radiation,Temozolomide
Treatment Location: Only at MDACC
Sponsor: STRATEGIC ALLIANCE: Genentech
1. Primary Phase I: To evaluate the safety of atezolizumab in combination with radiation and temozolomide during the concurrent stage and in combination with temozolomide during the adjuvant stage Phase II: To evaluate the overall survival (OS) of atezolizumab in combination with radiation and temozolomide and in combination with temozolomide at onset of treatment. 2. Secondary To evaluate the overall response rate (ORR), duration of response, and progression free survival (PFS) of atezolizumab in combination with radiation and temozolomide during the treatment period. 3. CORRELATIVE Profiling tumor immune cell populations (example: immunohistochemistry (IHC) analyses of CD4, CD8, programmed death-1(PD-1), programmed death-ligand 1 (PD-L1), and PD-L2). Profiling of tumor deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA) , microRNA and epigenetic profiling (DNA methylation) and evaluation of whole exome sequencing, RNA sequencing, microRNA sequencing and cell-free circulating tumor DNA (ctDNA). Peripheral blood collection for evaluation of circulating chemokines/cytokines.
IRB Review and Approval Date: 06/30/2017
Recruitment Status: Open
Projected Accrual: N/A
1) Signed Informed Consent Form (ICF)
2) Ability and willingness to comply with the requirements of the study protocol
3) Age >/= 18 years.
4) Have histologically confirmed World Health Organization Grade IV glioma (glioblastoma or gliosarcoma).
5) Patients must have undergone surgery and must not have had any further treatment following surgery.
6) Have a performance status of >/= 60 on the Karnosky Peformance Status (KPS).
7) A baseline brain MRI obtained no more than 14 days prior to study enrollment on a stable or tapering dose of steroids no greater than 4 mg a day of dexamethasone for at least 5 days.
8) Patients must start treatment within 6 weeks of definitive resection.
9) Demonstrate adequate organ function as defined in the following: Absolute neutrophil count (ANC) >/= 1,500 /mcL; Platelets >/= 100,000 /mcL; Hemoglobin >/= 9 g/dL or >/= 5.6 mmol/L; Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place of creatinine or CrCl) </=1.5 X upper limit of normal (ULN) OR >/= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN; Serum total bilirubin </= 1.5 X ULN OR Direct bilirubin </= ULN for subjects with total bilirubin levels > 1.5 ULN; AST (SGOT) and ALT (SGPT) </= 2.5 X ULN; International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) </=1.5 X ULN
10) Have provided tissue from an archival tissue sample.
11) All screening labs should be performed within 14 days (+3 working days) of treatment initiation.
12) Female subject of childbearing potential should have a negative serum pregnancy test within 14 days (+ 3 working days) of study enrollment.
13) Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the duration of the study. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
14) Male subjects should agree to use an adequate method of contraception during the course of the study.
1) Has received prior interstitial brachytherapy, implanted
chemotherapy, or therapeutics delivered by local injection or convection
enhanced delivery. Prior treatment with Gliadel® wafers will be
excluded. Prior treatment with the Optune® device will be excluded.
2) Is currently participating or has participated in any other newly diagnosed therapeutic trial before or after chemoradiation.
3) Any serious medical condition that interferes with adherence to study procedures.
4) Patients may not receive concomitant chemotherapy, hormonal therapy, immunotherapy, or radiotherapy while patients are on study.
5) Malignancies other than the disease under study within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0).
6) Has known gliomatous meningitis, extracranial disease, or multifocal disease. Subject has multifocal GBM, defined as discrete sites of disease without contiguous T2/FLAIR abnormality that require distinct radiotherapy ports. Satellite lesions that are associated with a contiguous area of T2/FLAIR abnormality as the main lesion(s) and that are encompassed within the same radiotherapy port as the main lesion(s) are permitted.
7) Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
8) Has an active infection requiring systemic therapy.
9) 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.
10) Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
11) Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit.
12) Contraindication for undergoing MRIs
13) Inability to comply with study and follow-up procedures
14) History or risk of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. o Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. o Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
15) (14. continued) o Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions: Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations; Rash must cover less than 10% of body surface area (BSA); Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%); No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids).
16) History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. o History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
17) Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
18) History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection. o Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible. Patients will be sampled for HBV DNA and will be referred to a virologist to monitor for HBV re-activation. o Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
19) Active tuberculosis
20) Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
21) Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
22) Received oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1. o Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible.
23) Anticipation of need for a major surgical procedure during the course of the study
24) Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live, attenuated vaccine will be required during the study. o Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist?) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study and for 5 months after last dose of atezolizumab.
25) Malignancies other than the disease under study within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score </= 6, and prostate-specific antigen [PSA] </= 10 mg/mL, etc.)
26) Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway targeting agents.
27) Treatment with systemic immunostimulatory agents (including but not limited to interferon [IFN]-a or interleukin [IL]-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1
28) Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1. o Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. o The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
29) History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
30) Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
Information and next steps
Malignant neoplasms of eye brain and other parts of central nervous system
Phase I/Phase II
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