Phase 2 and Biomarker Trial of Anti-TIGIT and Anti-PDL1 in Patients With Recurrent Glioblastoma
Overview
- Phase
- Phase 2
- Intervention
- Atezolizumab
- Conditions
- Recurrent Glioblastoma, IDH-Wildtype
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 52
- Primary Endpoint
- Progression free survival (PFS)
- Status
- Withdrawn
- Last Updated
- last year
Overview
Brief Summary
This phase II trial compares the safety, side effects and effectiveness of atezolizumab with tiragolumab to atezolizumab alone in treating patients with glioblastoma that has come back after a period of improvement (recurrent). Glioblastoma is the most common primary brain cancer in adults and despite aggressive treatment, it is nearly always fatal. Currently, there are limited effective treatment options in patients that have recurrence. Immunotherapy has been shown to be effective in other types of cancer and may be an appealing potential treatment option for recurrent glioblastoma. Immunotherapy with monoclonal antibodies, such as atezolizumab and tiragolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Study doctors also want to learn if a tumor infiltrating T lymphocyte (TIL) response is helpful to determine the benefit of the combination of study drugs compared to the usual approach. TILs are a type of immune cell that has moved from the blood into a tumor. TILs can recognize and kill tumor cells. Giving atezolizumab with tiragolumab may be safe, tolerable and/or effective compared to atezolizumab alone in treating patients with recurrent glioblastoma.
Detailed Description
PRIMARY OBJECTIVE: I. To evaluate the impact of combination atezolizumab plus tiragolumab on progression free survival. SECONDARY OBJECTIVES: I. To evaluate the impact of atezolizumab, tiragolumab, or their combination on tumor infiltrating T lymphocyte (TIL) density in glioblastoma patients. II. To evaluate the safety of study drug therapy in patients with glioblastoma in the (neo)adjuvant setting. III. To estimate therapeutic benefit of atezolizumab and tiragolumab in the recurrent glioblastoma patient population. IV. To evaluate the impact of baseline tumor mutation burden and expression on response. EXPLORATORY OBJECTIVES: I. To evaluate the impact of combination treatment on the tumor immune microenvironment. II. To evaluate the impact of combination treatment on the peripheral immune microenvironment. III. To evaluate the peripheral and central pharmacokinetics of tiragolumab and atezolizumab. OUTLINE: Patients are randomized to 1 of 4 groups. GROUP A: Patients receive atezolizumab intravenously (IV) over 60 minutes and tiragolumab IV over 20-75 minutes and 14-19 days later, undergo surgical resection. Following surgery, patients may receive tiragolumab IV and atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo magnetic resonance imaging (MRI) at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study. GROUP B: Patients receive tiragolumab IV over 20-75 minutes and 14-19 days later, undergo surgical resection. Following surgery, patients may receive tiragolumab IV and atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study. GROUP C: Patients receive atezolizumab IV over 60 minutes and 14-19 days later, undergo surgical resection. Following surgery patients may receive atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study. GROUP D: Patients undergo surgical resection on study. Following surgery patients may receive atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study. After completion of study treatment, patients are followed up at 30 days, and then every 3 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically confirmed IDH wildtype World Health Organization (WHO) grade IV glioblastoma at first or second relapse
- •Documented progression of disease as defined by modified Response Assessment in Neuro-Oncology (mRANO) criteria at least 12 weeks after completion of radiotherapy, unless the recurrence is outside the radiation field or has been histologically documented
- •Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of atezolizumab in combination with tiragolumab in patients \< 18 years of age, children are excluded from this study
- •Eastern Cooperative Oncology Group (ECOG) performance status \< 2 (Karnofsky ≥ 60%)
- •Leukocytes ≥ 2,000/mcL
- •Lymphocyte count ≥ 500/mcL
- •Absolute neutrophil count ≥ 1,500/mcL without granulocyte colony-stimulating factor support
- •Platelets ≥ 100,000/mcL without transfusion
- •Hemoglobin ≥ 9 g/dL
- •Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled)
Exclusion Criteria
- •Patients with IDH mutations will be excluded from the study
- •Patients who have had previous treatment with anti PD1, PDL1, CTLA-4 or other immune checkpoint inhibitors
- •Patients who have undergone tumor directed therapy for the most recent disease progression
- •Patients who have not recovered to grade 0 or 1 or pre-treatment baseline from clinically significant adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia
- •Patients who are receiving any other investigational agents
- •Patients with a diagnosis of immunodeficiency or who require treatment with high dose systemic corticosteroids defined as dexamethasone \> 2 mg/day or bioequivalent for at least 3 consecutive days within 1 week of start of study drug
- •Patients with severe, uncontrolled intercurrent illness, comorbidity, or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
- •Patients who are pregnant or breastfeeding or are expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 5 months after the last dose of study treatment. Women of childbearing potential (WOCPB) must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment. A WOCBP who has a positive urine pregnancy test (e.g., within 72 hours) prior to treatment will be excluded from the study. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a woman with a tubal ligation is considered to be of childbearing potential. The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Pregnant women are excluded from this study because atezolizumab and tiragolumab are monoclonal antibodies with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab and/or tiragolumab, breastfeeding should be discontinued if the mother is treated with atezolizumab and/or tiragolumab. To avoid pregnancy, WOCBPs and men must agree to use adequate contraception (i.e., contraceptive methods with a failure rate of \< 1% per year such as bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices) prior to the study, during treatment, and for 5 months after treatment ends. 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
- •Patients unable to comply with the protocol and/or not willing or who will not be available for follow-up assessments, specifically MRI scans
- •Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the exceptions listed below:
Arms & Interventions
GROUP A (neoadjuvant atezolizumab, tiragolumab)
Patients receive atezolizumab IV over 60 minutes and tiragolumab IV over 20-75 minutes and 14-19 days later, undergo surgical resection. Following surgery, patients may receive tiragolumab IV and atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Atezolizumab
GROUP A (neoadjuvant atezolizumab, tiragolumab)
Patients receive atezolizumab IV over 60 minutes and tiragolumab IV over 20-75 minutes and 14-19 days later, undergo surgical resection. Following surgery, patients may receive tiragolumab IV and atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Biospecimen Collection
GROUP A (neoadjuvant atezolizumab, tiragolumab)
Patients receive atezolizumab IV over 60 minutes and tiragolumab IV over 20-75 minutes and 14-19 days later, undergo surgical resection. Following surgery, patients may receive tiragolumab IV and atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
GROUP A (neoadjuvant atezolizumab, tiragolumab)
Patients receive atezolizumab IV over 60 minutes and tiragolumab IV over 20-75 minutes and 14-19 days later, undergo surgical resection. Following surgery, patients may receive tiragolumab IV and atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Surgical Procedure
GROUP A (neoadjuvant atezolizumab, tiragolumab)
Patients receive atezolizumab IV over 60 minutes and tiragolumab IV over 20-75 minutes and 14-19 days later, undergo surgical resection. Following surgery, patients may receive tiragolumab IV and atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Tiragolumab
GROUP B (neoadjuvant tiragolumab)
Patients receive tiragolumab IV over 20-75 minutes and 14-19 days later, undergo surgical resection. Following surgery, patients may receive tiragolumab IV and atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Biospecimen Collection
GROUP B (neoadjuvant tiragolumab)
Patients receive tiragolumab IV over 20-75 minutes and 14-19 days later, undergo surgical resection. Following surgery, patients may receive tiragolumab IV and atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Atezolizumab
GROUP B (neoadjuvant tiragolumab)
Patients receive tiragolumab IV over 20-75 minutes and 14-19 days later, undergo surgical resection. Following surgery, patients may receive tiragolumab IV and atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
GROUP B (neoadjuvant tiragolumab)
Patients receive tiragolumab IV over 20-75 minutes and 14-19 days later, undergo surgical resection. Following surgery, patients may receive tiragolumab IV and atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Surgical Procedure
GROUP B (neoadjuvant tiragolumab)
Patients receive tiragolumab IV over 20-75 minutes and 14-19 days later, undergo surgical resection. Following surgery, patients may receive tiragolumab IV and atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Tiragolumab
GROUP C (neoadjuvant atezolizumab)
Patients receive atezolizumab IV over 60 minutes and 14-19 days later, undergo surgical resection. Following surgery patients may receive atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Atezolizumab
GROUP C (neoadjuvant atezolizumab)
Patients receive atezolizumab IV over 60 minutes and 14-19 days later, undergo surgical resection. Following surgery patients may receive atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Biospecimen Collection
GROUP C (neoadjuvant atezolizumab)
Patients receive atezolizumab IV over 60 minutes and 14-19 days later, undergo surgical resection. Following surgery patients may receive atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
GROUP C (neoadjuvant atezolizumab)
Patients receive atezolizumab IV over 60 minutes and 14-19 days later, undergo surgical resection. Following surgery patients may receive atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Surgical Procedure
GROUP D (no neoadjuvant drug)
Patients undergo surgical resection on study. Following surgery patients may receive atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Atezolizumab
GROUP D (no neoadjuvant drug)
Patients undergo surgical resection on study. Following surgery patients may receive atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Biospecimen Collection
GROUP D (no neoadjuvant drug)
Patients undergo surgical resection on study. Following surgery patients may receive atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
GROUP D (no neoadjuvant drug)
Patients undergo surgical resection on study. Following surgery patients may receive atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Surgical Procedure
GROUP D (no neoadjuvant drug)
Patients undergo surgical resection on study. Following surgery patients may receive atezolizumab IV on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI at baseline, 24-72 hours after surgery, then every 9 weeks until progression and blood sample collection throughout the study.
Intervention: Tiragolumab
Outcomes
Primary Outcomes
Progression free survival (PFS)
Time Frame: Up to 36 months
Will be assessed and compared between adjuvant arms. PFS will be assessed using Kaplan-Meier method.
Secondary Outcomes
- Dose limiting toxicity(Up to 30 completion of adjuvant cycle 2)
- Objective response rate (ORR)(Up to 36 months)
- Incidence of adverse events(Up to 30 days after last dose of study treatment)
- PFS6(At 6 months)
- Overall survival(Up to 36 months)
- Expression of immune checkpoint receptors and ligands(Up to 36 months)
- Tumor infiltrating T lymphocyte density(Up to 36 months)
- Tumor mutational burden (TMB)(Up to 36 months)