Pembrolizumab in Treating Patients with Recurrent / Progressive Glioblastoma That Can Be Accessed by Surgery
- 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
- Be willing and able to provide written informed consent/assent for the trial
- Have a Karnofsky performance status (KPS) >= 70
- Previous first line therapy with at least radiotherapy
- Be at first or second relapse; Note: relapse is defined as progression following initial therapy (i.e., radiation +/- chemotherapy); for participants who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse
- Participants must have shown unequivocal evidence for tumor progression by MRI or computed tomography (CT) scan
- Absolute neutrophil count (ANC) >= 1.5 K/uL (performed within 14 days of registration)
- Platelets >= 100 K/uL (performed within 14 days of registration)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (performed within 14 days of registration)
- Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) OR measured or calculated creatinine clearance (CrCl) (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (performed within 14 days of registration) * Creatinine clearance should be calculated per institutional standard
- Serum total bilirubin =< 1.5 x institutional ULN OR direct bilirubin =< institutional ULN for subjects with total bilirubin levels > 1.5 institutional ULN (performed within 14 days of registration)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN OR =< 5 x institutional ULN for subjects with Gilbert syndrome (performed within 14 days of registration)
- Albumin >= 2.5 mg/dL (performed within 14 days of registration)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x institutional ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 14 days of registration)
- Activated partial thromboplastin time (aPTT) =< 1.5 x institutional 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 of registration)
- CT or MRI within 14 days prior of registration; NOTE: Due to the fact that the screening MRI will not be used for response purposes, participants may be registered if screening CT or MRI is > 14 days of registration if prospective approval is received from overall principal investigator (PI), Dr. Patrick Wen (for prospectively approved circumstances an eligibility exception will not need to be filed)
- An interval of at least 4 weeks (to registration) between prior surgical resection or one week for stereotactic biopsy
- An interval of at least 12 weeks from the completion of radiation therapy to registration unless there is unequivocal histologic confirmation of tumor progression
- Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically significant toxic effects of prior therapy (including but not limited to exceptions of alopecia, laboratory values listed per inclusion criteria, and lymphopenia which is common after therapy with temozolomide)
- From registration, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies (including vaccines); no wash-out period required from time to treatment failure (TTF)
- Participants must have sufficient tissue from most recent surgery revealing glioblastoma or variants for submission following registration. The following amount of tissue is required: * 1 formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred)
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the trial are eligible * NOTE: Consultation with the overall PI is highly recommended if enrollment of a patient with a prior or concurrent malignancy will be pursued
- Patients must be undergoing surgery that is clinically indicated as determined by their care providers; patients must be eligible for surgical resection with the expectation that the surgeon is able to resect at least 400 mg of tumor with low risk of inducing neurological injury
- Female subjects of childbearing potential must have a negative urine or serum pregnancy within 72 hours prior to registration; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required; women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential
- Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must agree to use highly effective contraception during study treatment and for 120 days after study discontinuation; highly effective contraception is defined as either: * True Abstinence: When this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Sterilization: Surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner must be the sole partner for that participant * Use of a combination of any two of the following: ** Placement of an intrauterine device (IUD) or intrauterine system (IUS) ** Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository ** Appropriate hormonal contraceptives (including any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent – including oral, subcutaneous, intrauterine, or intramuscular agents)
- Male subjects must agree to use adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of therapy
- Current or planned participation in a study of an investigational agent or using an investigational device
- Has a diagnosis of immunodeficiency
- Has tumor primarily localized to the brainstem or spinal cord
- Has presence of diffuse leptomeningeal disease or extracranial disease
- Has received systemic immunosuppressive treatments, aside from systemic corticosteroids (such as methotrexate, chloroquine, azathioprine, etc) within six months of registration
- Has received anti-angiogenic or anti-VEGF targeted agents (e.g. bevacizumab, cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc)
- Requires treatment with high dose systemic corticosteroids defined as dexamethasone > 4 mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of registration
- Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic radiosurgery or therapeutics delivered by local injection or convection enhanced delivery
- Has history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of registration
- Has a known history of active TB (Bacillus tuberculosis)
- Has gastrointestinal bleeding or any other hemorrhage/bleeding event Common Terminology Criteria for Adverse Events (CTCAE) grade > 3 within 6 months of registration
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Has known history of, or any evidence of active non-infectious pneumonitis
- Has an active infection requiring systemic therapy
- 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; examples include but are not limited to symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B virus HBsAg surface protein antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C viral load measurement [HCV RNA] [qualitative] is detected)
- Has received a live vaccine within 30 days prior to registration
- Has a known hypersensitivity to any of the study therapy products
Salt Lake City
I. To test the hypothesis that administration of pembrolizumab (MK-3475) will induce statistically significant increases in tumor infiltrating T lymphocyte (TIL) density in recurrent/progressive glioblastoma multiform (GBM) patients compared to an untreated concurrent control versus the null hypothesis of no difference the treatment and control groups. (Group A versus [vs.] Group B) (Stage I)
II. To test the hypothesis that administration of pembrolizumab (MK-3475) will lead to statistically significant changes, specifically decreased expression of the cell cycle/cancer proliferation related genetic signatures, within the tumor mircroenvironment of recurrent/progressive GBM when compared to an untreated concurrent control versus the null hypothesis of no difference the treatment and control groups. (Group A vs. Group B) (Stage II)
II. To evaluate safety of study drug in this patient population. (Stages I and II)
I. To estimate percent progression free survival at 6 months (PFS6) in this patient population using Response Assessment in Neuro-Oncology (RANO) criteria.
I. To evaluate the associations between exploratory biomarkers and clinical outcomes and adverse events - these include:
Ia. Estimate correlation of quantitative assessments of TIL density or clonality with clinical responses to pembrolizumab in recurrent glioblastoma patients.
Ib. Estimate efficacy of pembrolizumab by PFS, second PFS and overall survival (OS) (Groups A and B) as defined by RANO.
Ic. Estimate efficacy of pembrolizumab by PFS6, PFS, second PFS and OS (Groups A and B) as defined by immunotherapy RANO (iRANO).
Id. Explore effect of pembrolizumab on TIL proliferation (CD8 + KI-67+ staining).
Ie. Estimate difference in PD-1 and PDL-1 immunohistochemistry (IHC) expression between Group A and B as well as between archived and study samples.
If. Explore whether oligoclonal T cell populations within tumor tissue are similarly expanded in peripheral blood after pembrolizumab, the magnitude of which correlates with clinical responses.
Ig. Explore if changes in specific magnetic resonance imaging (MRI) parameters correlate with tumor and peripheral blood immune responses.
If. Correlation of tumor messenger ribonucleic acid (mRNA) from extracellular vesicles with outcome.
OUTLINE: Patients are randomized to 1 of 2 treatment groups.
GROUP A: Patients receive pembrolizumab intravenously (IV) over 30 minutes within 14 days before surgery. Beginning no more than 35 days after tumor resection, patients receive pembrolizumab IV over 30 minutes on days 1 and 22. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.
GROUP B: Beginning no more than 35 days after tumor resection, patients receive pembrolizumab IV over 30 minutes on days 1 and 22. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 and 90 days and then every 3 months.
Trial Phase Phase I
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Patrick Yung Chih Wen
- Primary ID 16-225
- Secondary IDs NCI-2016-01480
- Clinicaltrials.gov ID NCT02852655