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Atezolizumab (aPDL1) + Temozolomide and Radiation for Newly Diagnosed Glioblastoma (GBM)

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ClinicalTrials.gov Identifier: NCT03174197
Recruitment Status : Recruiting
First Posted : June 2, 2017
Last Update Posted : November 14, 2017
Sponsor:
Collaborator:
Information provided by (Responsible Party):

Study Description
Brief Summary:

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.

This is an investigational study. Atezolizumab is FDA approved and commercially available for the treatment of several types of cancer, but not glioblastoma. Temozolomide is FDA approved and commercially available for the treatment of glioblastoma. The radiation therapy used in this study is being delivered using FDA-approved and commercially available methods.

It is considered investigational to use atezolizumab in combination with temozolomide and radiation therapy to treat glioblastoma.

The study doctor can describe how the study drugs and radiation are designed to work.

Up to 60 participants will be enrolled in this study. All will take part at MD Anderson.


Condition or disease Intervention/treatment Phase
Malignant Neoplasms of Eye Brain and Other Parts of Central Nervous System Glioblastoma Gliosarcoma Drug: Temozolomide Drug: Atezolizumab Radiation: Radiation Therapy Phase 1 Phase 2

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Detailed Description:

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study phase based on when you join the study. The first 10 participants enrolled will take part in Part I of the study. Up to 50 additional participants will take part in Part II of the study.

All participants will receive the same dose of atezolizumab, temozolomide, and radiation therapy.

Study Drug Administration:

Treatment will be given in 2 phases: Concurrent Phase and Adjuvant Phase.

Concurrent Phase:

There are 42 days (about 6 weeks) in the concurrent phase.

You will take temozolomide capsules by mouth every day. Do not open the capsules. If the capsules are accidentally opened or damaged, you should avoid inhaling or coming into contact with the contents of the capsule.

You will also receive atezolizumab by vein over about 60 minutes on Day 1. If you tolerate the drug well, it may be given over about 30 minutes after that on Days 15, 29, and 42 (about every 2 weeks).

You will receive radiation therapy Monday through Friday every week as part of your standard care. You will sign a separate consent form for the radiation therapy that explains this treatment and its risks in more detail.

After you finish radiation therapy, you will have a break or "rest period" for about 21-28 days in which you do not take temozolomide or atezolizumab.

Adjuvant Phase:

Each study cycle in the adjuvant phase is 28 days.

You will take temozolomide by mouth on Days 1-5 of each cycle. You will receive atezolizumab by vein over about 30 minutes on Days 1 and 15 of each cycle.

You will not receive radiation therapy during the adjuvant phase of the study.

Length of Study:

You may receive temozolomide and atezolizumab for up to 12 cycles. You may receive radiation therapy for up to 6 weeks. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Study Visits:

Concurrent Phase:

On Days 1, 8, 15, 22, 29, 35 and 42:

  • Blood (about 1 teaspoon) will be drawn for routine tests.
  • On Day 22 only, you will have a physical exam, including a neurological exam.
  • On Day 1 only, if you can become pregnant, blood (about ½ teaspoon) will be drawn for a pregnancy test.

Adjuvant Phase:

On Day 1 of each cycle:

  • You will have a physical exam, including a neurological exam.
  • Blood (about 2 teaspoons) will be drawn for routine tests. This sample will also be used for a pregnancy test, if you can become pregnant.
  • Blood (about 4 tablespoons) will be drawn for biomarker testing (Cycles 1 and 3 only).
  • During odd-numbered cycles (Cycles 1, 3, 5 and so on) only, you will have an MRI.

On Day 21 of each cycle, blood (about 1 teaspoon) will be drawn for routine tests.

At any time during the study, extra tests may be performed if the doctor thinks they are needed. The study doctor will tell you more about any extra tests that may be needed.

End-of-Treatment Visit:

Within 30 days after your last dose of study drugs:

  • You will have a physical exam, including neurological exam.
  • Blood (about 3 teaspoons) will be drawn for routine tests. This sample will also be used for a pregnancy test, if you can become pregnant.
  • You will have an MRI.

If the disease gets worse at any time while you are on study, blood (about 4tablespoons) will be drawn for biomarker testing. If you have surgery as part of your standard care, additional tumor tissue will be collected for biomarker testing, including genetic biomarkers.

Follow-Up:

About every 3 months after your last dose of study drugs, the study staff will call you or check your medical records to learn how you are doing. If you are called, the call should take about 5-10 minutes.

If you stop taking the study drug and the disease has not gotten worse, you will have the following as often as the doctor thinks is needed:

  • You will have a physical exam.
  • Blood (about 2 teaspoons) will be drawn for routine tests.
  • You will have an MRI scan.

The study doctor will discuss with you how often these tests may be performed. If the disease gets worse or the study ends, you will no longer have these tests for the study.


Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : June 30, 2017
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2020


Arms and Interventions

Arm Intervention/treatment
Experimental: Concurrent Phase Group

There are 42 days (about 6 weeks) in the Concurrent Phase. Group consists of 10 participants for this safety run-in stage.

Temozolomide capsules taken by mouth every day.

Atezolizumab given by vein on Day 1. If drug tolerated well, it may be given after that on Days 15, 29, and 42 (about every 2 weeks).

Radiation therapy delivered Monday through Friday every week for 6 weeks as part of standard care.

After radiation therapy completed, participants have a break or "rest period" for about 21-28 days in which neither Temozolomide or Atezolizumab is received.

Drug: Temozolomide

Concurrent Phase Group: Temozolomide 75 mg/m2 capsules taken by mouth every day for 6 weeks.

Adjuvant Phase Group: Temozolomide 150 mg/m2 capsules taken by mouth on Days 1-5 every 28 days.

Other Names:
  • Temodar
  • TMZ
Drug: Atezolizumab

Concurrent Phase Group: Atezolizumab 840 mg given by vein on Day 1. If drug tolerated well, it may be given after that on Days 15, 29, and 42 (about every 2 weeks).

Adjuvant Phase Group: Atezolizumab 840 mg given by vein every 2 weeks for up to 12 cycles of therapy until there is evidence of disease progression.

Other Name: MPDL3280A
Radiation: Radiation Therapy
Radiation therapy administered using 1.8-2 Gy/fraction daily for 5 days/week for ~6 weeks for a total dose of up to 60 Gy.
Other Names:
  • External beam
  • XRT
Experimental: Adjuvant Phase Group

Each study cycle in the Adjuvant Phase is 28 days.

Temozolomide taken by mouth on Days 1-5 of each cycle.

Atezolizumab given by vein over about 30 minutes on Days 1 and 15 of each cycle.

Temozolomide and Atezolizumab given for up to 12 cycles.

Drug: Temozolomide

Concurrent Phase Group: Temozolomide 75 mg/m2 capsules taken by mouth every day for 6 weeks.

Adjuvant Phase Group: Temozolomide 150 mg/m2 capsules taken by mouth on Days 1-5 every 28 days.

Other Names:
  • Temodar
  • TMZ
Drug: Atezolizumab

Concurrent Phase Group: Atezolizumab 840 mg given by vein on Day 1. If drug tolerated well, it may be given after that on Days 15, 29, and 42 (about every 2 weeks).

Adjuvant Phase Group: Atezolizumab 840 mg given by vein every 2 weeks for up to 12 cycles of therapy until there is evidence of disease progression.

Other Name: MPDL3280A


Outcome Measures

Primary Outcome Measures :
  1. Dose Limiting Toxicity (DLT) of Atezolizumab for Newly Diagnosed Glioblastoma (GBM) [ Time Frame: 10 weeks ]

    DLT defined as a clinically significant adverse event (AE) considered at least possibly related to study drug during the first 10 weeks of study treatment.

    AEs evaluated in this study through the monitoring of all serious and non-serious AEs, defined and graded according to NCI CTCAE v4.0.


  2. Overall Survival (OS) of Atezolizumab and Temozolomide in Combination with Radiation for Newly Diagnosed Glioblastoma (GBM) [ Time Frame: 20 months ]
    OS distribution estimated using the Kaplan-Meier method.


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) of Atezolizumab in Combination with Radiation and Temozolomide During Treatment Period [ Time Frame: 6 weeks ]
    ORR defined as number of patients with partial response (PR) and complete response (CR) maintained for a minimum of 6 weeks assessed by Response Assessment in Neuro-Oncology (RANO) working group.


Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  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 Karnofsky Performance 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 calculated 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.

Exclusion Criteria:

  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. Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
  15. (14. continued) 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%, fluocinolone 0.01%, desonide 0.05%, alclometasone 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. 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. 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. 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. 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. 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. Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. 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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03174197


Contacts
Contact: Shiao-Pei Weathers, MD 713-792-2883 CR_Study_Registration@mdanderson.org
Contact: Betsy Williams, MSN, BSN, AAS 713-792-2883

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Clinical Research Operations       CR_Study_Registration@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
Genentech, Inc.
Investigators
Principal Investigator: Shiao-Pei Weathers, MD M.D. Anderson Cancer Center
More Information

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03174197     History of Changes
Other Study ID Numbers: 2016-0867
NCI-2017-01619 ( Registry Identifier: NCI CTRP )
First Posted: June 2, 2017    Key Record Dates
Last Update Posted: November 14, 2017
Last Verified: November 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Malignant neoplasms of eye brain and other parts of central nervous system
Glioblastoma (GBM)
GBM
Gliosarcoma
Temozolomide
Temodar
TMZ
Atezolizumab
MPDL3280A
Radiation therapy
External beam
XRT

Additional relevant MeSH terms:
Glioblastoma
Neoplasms
Gliosarcoma
Eye Neoplasms
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Eye Diseases
Temozolomide
Dacarbazine
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs