Pharmacodynamic Study of Pembrolizumab in Patients with Recurrent Glioblastoma
The goal of this clinical research study is to learn if Keytruda (pembrolizumab) can help to control glioblastoma. The safety of this drug will also be studied.
Disease Group: Brain,CNS
Treatment Agent: MK-3475
Treatment Location: Only at MDACC
Sponsor: MDACC Glioblastoma Moon Shot program.,Merck
1. Primary Objective The co-primary objectives of this study are to 1) evaluate immune effector function in resected glioblastoma tissue after treatment with intravenously administered pembrolizumab monotherapy in the neoadjuvant setting in patients with recurrent glioblastoma and 2) to correlate the progression free survival at 6 months (PFS6) with objective increases in the immune effector Tcell:Treg ratio in tumor tissue as measured by ex vivo T-cell-specific cytokines profiling. 2. Secondary Objective The secondary objectives include 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. 3. Exploratory Objective To identify imaging characteristics associated with immunological changes in tumor following treatment with pembrolizumab .
IRB Review and Approval Date: 04/28/2015
Recruitment Status: Open
Projected Accrual: N/A
1) Be willing and able to provide written informed consent/assent for
2) Be >/= 18 years of age on day of signing informed consent.
3) Have histiologically 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 histiological diagnosis of glioblastoma or variants is made.
4) 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 antitumor 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.
5) Have measurable disease consisting of a minimal volume of 1 cm3.
6) Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion.
7) Have a performance status of >/= 60 on the KPS.
8) Stable dose of steroids for 5 days, no more than 2 mg dexamethasone (or equivalent) total per day
9) Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 14 days prior to registration. 1) Hematological : Absolute neutrophil count (ANC) >/=1,500 /mcL; Platelets >/=100,000 / mcL; Hemoglobin >/= 9 g/dL or >/= 5.6 mmol/L. 2) Renal: Serum creatinine </= 1.5 X upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) >/= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN.
10) (9. continued) 3) Hepatic: 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 OR </= 5 X ULN for subjects with liver metastases. 4) Coagulation: 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; 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.
11) Female subject of childbearing potential should have a negative serum pregnancy test.
12) 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.
13) 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.
1) Has been treated previously with bevacizumab
2) Has tumor localized primarily to the brainstem or spinal cord.
3) Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics delivered by local injection or convection enhanced delivery.
4) 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.
5) 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.
6) 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.
7) 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.
8) 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.
9) Has known carcinomatous meningitis, extracranial diseaese, or multifocal disease.
10) 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 Sjorgen’s syndrome will not be excluded from the study.
11) Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
12) Has an active infection requiring systemic therapy.
13) 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.
14) Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
15) 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.
16) Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
17) Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Testing not required.
18) Has known history of Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). Testing not required.
19) Has received a live vaccine within 30 days prior to the first dose of trial treatment.
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