Pembrolizumab in Treating Patients With Recurrent Glioblastoma
Study Details
Study Description
Brief Summary
This phase II trial studies the effects of pembrolizumab on the body, or pharmacodynamics, in patients with glioblastoma that has come back. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
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To evaluate immune effector function in resected glioblastoma tissue after treatment with intravenously administered pembrolizumab monotherapy in the neoadjuvant setting in patients with recurrent glioblastoma.
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To correlate the progression free survival at 6 months (PFS6) with objective increases in the immune effector T cell: regulatory T cell (Treg) ratio in tumor tissue as measured by ex vivo T-cell-specific cytokines profiling.
SECONDARY OBJECTIVES:
- Comparison of time to progression of last prior therapy to time to progression on pembrolizumab, median duration of response, overall response rate (ORR), and overall survival (OS) and safety.
TERTIARY OBJECTIVES:
- To identify imaging characteristics associated with immunological changes in tumor following treatment with pembrolizumab.
OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day -21 and day -1, and then undergo surgery on day 0. After 2-3 weeks or recovery from surgery, patients continue to receive pembrolizumab IV over 30 minutes every 3 weeks. Courses repeat every 42 days for up to 24 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (pembrolizumab, surgery) Patients receive pembrolizumab IV over 30 minutes on day -21 and day -1, and then undergo surgery on day 0. After 2-3 weeks or recovery from surgery, patients continue to receive pembrolizumab IV over 30 minutes every 3 weeks. Courses repeat every 42 days for up to 24 months in the absence of disease progression or unacceptable toxicity. |
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Pembrolizumab
Given IV
Other Names:
Other: Pharmacological Study
Correlative studies
Procedure: Therapeutic Conventional Surgery
Undergo surgery
|
Outcome Measures
Primary Outcome Measures
- Progression free survival at 6 months [At 6 months]
Progression free survival at 6 months will be estimated using Kaplan-Meier estimates and associated two-sided 95% confidence intervals.
Secondary Outcome Measures
- Time to progression [The time from study enrollment until the time of first occurrence of disease progression, relapse, or death due to disease, assessed up to 2 years]
Evaluated using the Kaplan-Meier product-limit survival curve methodology. Cox proportional hazard regression will be employed for multivariate analysis.
- Overall survival [Up to 2 years]
Evaluated using the Kaplan-Meier product-limit survival curve methodology. Cox proportional hazard regression will be employed for multivariate analysis.
- Response rate [Up to 2 years]
Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate.
- Rate of toxicities [Up to 30 days after completion of study treatment]
Logistic regression will be utilized to assess the effect of patient prognostic factors on the toxicity rate.
- Changes in peripheral blood mononuclear cells immune response kinetics [Baseline to up to 24 months]
Presented graphically and descriptively at each time point. Changes in the magnitude of the response relative to pretreatment after pembrolizumab therapy will be summarized descriptively. Changes in response between pre-treatment and prior to initiation of course 3 of pembrolizumab will be assessed using the Wilcoxon signed-rank test.
- Changes in circulating cytokines to pembrolizumab [Baseline to up to 24 months]
Presented graphically and descriptively at each time point. Changes in the magnitude of the response relative to pretreatment after pembrolizumab therapy will be summarized descriptively. Changes in response between pre-treatment and prior to initiation of course 3 of pembrolizumab will be assessed using the Wilcoxon signed-rank test.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Be willing and able to provide written informed consent/assent for the trial
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Have histologically confirmed World Health Organization grade IV malignant glioma (glioblastoma or gliosarcoma); participants will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of glioblastoma or variants is made
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Patients must be at first or second relapse and clinically require reoperation for tumor progression within 4 to 6 weeks; Note: relapse is defined as progression following initial therapy (i.e., radiation, chemotherapy, or radiation + chemotherapy); if the participant had a surgical resection for relapsed disease and no anti-tumor therapy instituted for up to 12 weeks, this is considered one relapse; for participants who had prior therapy for a low grade glioma, the surgical diagnosis of a high grade glioma will be considered first relapse
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Have measurable disease consisting of a minimal volume of 1 cm^3
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Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion
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Have a performance status of >= 60 on the Karnofsky performance scale (KPS)
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Stable dose of steroids for 5 days, no more than 2 mg dexamethasone (or equivalent) total per day
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Absolute neutrophil count (ANC) >= 1,500/mcL (performed within 14 days prior to registration)
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Platelets >=100,000/mcL (performed within 14 days prior to registration)
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Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (performed within 14 days prior to registration)
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Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (performed within 14 days prior to registration)
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Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 14 days prior to registration)
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Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (performed within 14 days prior to registration)
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International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 14 days prior to registration)
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Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 14 days prior to registration)
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Female subject of childbearing potential should have a negative serum pregnancy test
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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 course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
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Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
Exclusion Criteria:
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Has been treated previously with bevacizumab
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Has tumor localized primarily to the brainstem or spinal cord
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Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics delivered by local injection or convection enhanced delivery
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Is currently participating in or has participated in a study of an investigational agent or using an investigational device 4 weeks since last dose of agent administration
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Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy > 2 mg of dexamethasone total per day or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
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Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
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Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent; Note: subjects with alopecia, =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
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Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
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Has known carcinomatous meningitis, extracranial disease, or multifocal disease
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Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study
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Has evidence of interstitial lung disease or active, non-infectious pneumonitis
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Has an active infection requiring systemic therapy
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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
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Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
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Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment
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Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD ligand (PD-L)1, anti-PD-L2, anti-cluster of differentiation (CD)137 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
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Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies); testing not required
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Has known history of hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected); testing not required
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Has received a live vaccine within 30 days prior to the first dose of trial treatment
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | M D Anderson Cancer Center | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- M.D. Anderson Cancer Center
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Vinay Puduvalli, MD, M.D. Anderson Cancer Center
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 2014-0820
- NCI-2015-00174
- 2014-0820
- P30CA016672