Autologous CMV-Specific Cytotoxic T Cells and Temozolomide in Treating Patients With Glioblastoma

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of autologous cytomegalovirus (CMV)-specific cytotoxic T cells when given together with temozolomide and to see how well they work in treating patients with glioblastoma. Autologous CMV-specific cytotoxic T cells may stimulate the immune system to attack specific tumor cells and stop them from growing or kill them. Drugs used in chemotherapy, such as temozolomide, may work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving autologous CMV-specific cytotoxic T cells with temozolomide may be a better treatment for patients with glioblastoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum feasible dose (MFD) or maximum tolerated dose (MTD) and safety of cytomegalovirus (CMV)-specific T cells in combination with dose-dense temozolomide in patients with recurrent glioblastoma. (Phase I) II. To evaluate the immunological effects in resected glioblastoma after intravenous administered cytomegalovirus (CMV)-stimulated adoptive T cells in patients with recurrent glioblastoma (GBM). (Phase II: recurrent glioblastoma undergoing resection) III. To correlate 6-month progression-free survival rate (PFS6) with objective clearance of CMV antigens as measured by immunohistochemistry (IHC) and by ex vivo T-cell-specific effector responses using intracellular cytokine profiling. (Phase II: recurrent glioblastoma undergoing resection) IV. Overall survival (OS). (Phase II: newly diagnosed glioblastoma) SECONDARY OBJECTIVES: I. Time to progression, overall survival (OS) as well as immunological reactivity and safety. (Phase II: recurrent glioblastoma undergoing resection) II. Safety and tolerability of dose-dense temozolomide in combination with intravenous administered CMV-stimulated adoptive T cells in patients receiving adjuvant therapy after completing external beam radiotherapy with concurrent temozolomide for newly diagnosed glioblastoma. (Phase II: newly diagnosed glioblastoma) III. Overall objective response rate (ORR), median duration of response, PFS6. (Phase II: newly diagnosed glioblastoma) EXPLORATORY OBJECTIVES: I. To determine the persistence and expansion of adoptively-infused CMV-specific T cells by multiparameter flow cytometry in serially-sampled peripheral blood. (Phase I) II. To identify imaging characteristics such as magnetic resonance imaging (MRI) textural analysis associated with immunological changes in tumor following treatment with CMV-stimulated adoptive T cells. (Phase II: recurrent glioblastoma undergoing resection) III. To ascertain if adoptive transfer of CMV-specific T cells leads to the expansion of T cells with specificity to other glioblastoma antigens (i.e. epitope spreading) by performing longitudinally monitoring of antigen-specific T cell frequency with enzyme-linked immunosorbent spot assay (ELISPOT). (Phase II: recurrent glioblastoma undergoing resection) IV. To determine the persistence and expansion of adoptively-infused CMV-specific T cells by multiparameter flow cytometry in serially-sampled peripheral blood. (Phase II: newly diagnosed glioblastoma) OUTLINE: This is a phase I, dose-escalation study of CMV-specific T cells followed by a phase II study. Patients are assigned to 1 of 2 treatment arms. ARM I: Patients receive temozolomide orally (PO) once a day (QD) on days 1-21 and CMV-specific T cell transfer intravenously (IV) over 1-5 minutes on day 22. Patients undergo surgery on day 30 of cycle 1. Treatment repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive temozolomide PO QD on days 1-21. Treatment repeats every 42 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive temozolomide PO QD on days 1-21 and CMV-specific T cell transfer intravenously IV over 1-5 minutes on day 22. Treatment repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and every 3 months.

Official Title
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A Phase I/II Clinical Trial of Autologous CMV-Specific Cytotoxic T Cells for GBM Patients

Conditions
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Cytomegalovirus Positive, Glioblastoma, Gliosarcoma, Malignant Glioma, Recurrent Brain Neoplasm, Recurrent Glioblastoma

Intervention / Treatment
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* Biological: Autologous Cytomegalovirus-specific Cytotoxic T-lymphocytes
* Other: Laboratory Biomarker Analysis
* Drug: Temozolomide
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be willing and able to provide written informed consent for the trial PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Have histologically confirmed World Health Organization grade IV malignant glioma (glioblastoma or gliosarcoma); participants will also be eligible if the original histology was lower grade glioma and there is suspected transformation to glioblastoma based on imaging findings; if the final pathology report after resection fails to confirm recurrent glioblastoma or gliosarcoma, the subject will be followed for adverse events (AEs) and survival, but excluded for other primary and secondary objective analysis; the subject will be replaced PHASE II DOSE EXPANSION IN NEWLY DIAGNOSED GBM: Have histologically confirmed World Health Organization grade IV glioma (glioblastoma or gliosarcoma) PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Be at first relapse; Note: relapse is defined as progression following initial therapy (i.e., radiation, chemotherapy, or radiation plus (+) 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 lower grade glioma, the surgical diagnosis of glioblastoma or gliosarcoma will be considered first relapse PHASE II DOSE EXPANSION IN NEWLY DIAGNOSED GBM: Patients must have completed standard radiation therapy with concurrent temozolomide (TMZ) within 5 weeks (wks) of enrollment and must not have evidence of progressive disease on post treatment imaging; progression can only be defined using diagnostic imaging if there is new enhancement outside of the radiation field (beyond the high-dose region or 80% isodose line) or if there is unequivocal evidence of viable tumor on histopathologic sampling (e.g., solid tumor areas [i.e,> 70% tumor cell nuclei in areas], high or progressive increase in mindbomb homolog 1[MIB-1] proliferation index compared with prior biopsy, or evidence for histologic progression or increased anaplasia in tumor); Note: given the difficulty of differentiating true progression from pseudoprogression, clinical decline alone, in the absence of radiographic or histologic confirmation of progression, will not be sufficient for definition of progressive disease in the first 12 weeks after completion of concurrent chemoradiotherapy PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Have measurable disease consisting of a minimal volume of 1 cm^3 CMV seropositive PHASE I AND PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Be willing to provide tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion PHASE II DOSE EXPANSION IN NEWLY DIAGNOSED GBM: Be willing to provide tissue from an archival tissue sample Have a performance status of >= 60 on the Karnofsky performance status (KPS) If patient is on steroids, patient must be on a stable or decreasing dose of steroids for 5 days, no more than 2 mg dexamethasone (or equivalent) total per day at the time of screening and consent; if on steroids at the time of screening, the dose will need to be tapered and discontinued at least 5 days prior to CMV T cell infusion Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 14 days [+3 working days] of treatment initiation) Platelets >= 100,000 / mcL (performed within 14 days [+3 working days] of treatment initiation) Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (performed within 14 days [+3 working days] of treatment initiation) Serum creatinine OR measured or calculated (creatinine clearance should be calculated per institutional standard) creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 X upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (performed within 14 days [+3 working days] of treatment initiation) Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 14 days [+3 working days] of treatment initiation) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN (performed within 14 days [+3 working days] of treatment initiation) Coagulation international normalized ratio (INR) or prothrombin time (PT), activated partial thromboplastin time (aPTT) =< 1.5 X ULN (performed within 14 days [+3 working days] of treatment initiation) Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours of study enrollment; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required Female subjects of childbearing potential should be willing to use 2 methods of birth control during the study and for 30 days after the last dose of the study drug or be surgically sterile; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year Male subjects should agree to use an adequate method of contraception during the course of the study and for 30 days after the last dose of the study drug PHASE I: Have histologically confirmed World Health Organization WHO grade IV 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 PHASE I: A baseline brain MRI must be obtained no more than 14 days (+ 3 working days) prior to study enrollment; the patient must either be on no steroids or a stable dose of dexamethasone no greater than 2 mg a day for at least 5 days prior to entrance onto the study; patients having undergone recent surgery are eligible as long as they are at least 3 weeks from resection or 1 week from stereotactic biopsy, and recovering from any operative or perioperative complications; no measurable disease post resection will be required PHASE 1: Patients having undergone recent surgery are eligible as long as they are at least 3 weeks from resection or 1 week from stereotactic biopsy, and recovering from any operative or perioperative complications; no measurable disease post resection will be required PHASE I: Any number of prior relapses PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: A baseline brain MRI must be obtained no more than 14 days (+ 3 working days) prior to study enrollment; the patient must either be on no steroids or a stable dose of dexamethasone no greater than 2 mg a day for at least 5 days prior to entrance onto the study PHASE II DOSE EXPANSION IN NEWLY DIAGNOSED GBM: A baseline brain MRI obtained no more than 14 days (+ 3 working days) prior to study enrollment on a stable dose of steroids no greater than 2 mg a day of dexamethasone for at least 5 days, is required prior to entrance of a patient onto the study; patients must be registered on the study within 5 weeks of completion of concurrent chemoradiation Exclusion Criteria: Has been treated previously with bevacizumab PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Has tumor localized primarily to the posterior fossa, spinal cord, or an unresectable location 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 PHASE I AND PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Is =< 12 weeks from completing external beam radiotherapy; patients with proven progressive disease (PD) by resection or with new lesions outside of the radiation field should not be excluded even if they are within 12 weeks of external radiation therapy (XRT), per Response Assessment in Neuro-Oncology (RANO) criteria for early PD PHASE I AND PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Is currently participating in a study of an investigational agent or using an investigational device for therapeutic purposes; concurrent use of Optune device is not allowed PHASE II DOSE EXPANSION IN NEWLY DIAGNOSED GBM: Is currently participating or has participated in any other newly diagnosed therapeutic trial before or after chemoradiation CMV seronegative Has a known history of human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies); human T-cell lymphotropic virus (HTLV) 1 antibody (HTLV1) and/or HTLV2; active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected); patients with prior hepatitis B virus (HBV) vaccination (anti-hepatitis B surface antibody [HBs] positive, HBsAg negative, anti-hepatitis B core antibody [HBc] negative) will NOT be excluded Has a diagnosis of immunodeficiency or is receiving systemic immunosuppressive therapy within 7 days of study entrance PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Has had prior chemotherapy, or targeted small molecule 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 =< grade 2 neuropathy are an exception to this criterion and may qualify for the study; Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy 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 PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Has known gliomatous meningitis, subependymal spread, extracranial disease, or multifocal disease PHASE II DOSE EXPANSION IN NEWLY DIAGNOSED GBM: Has known gliomatous meningitis, extracranial disease, or multifocal disease 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 Has evidence of interstitial lung disease or 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 Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION AND IN NEWLY DIAGNOSED GBM: Has received prior therapy with any antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways Has received a live vaccine within 30 days prior to the first dose of trial treatment Contraindication for undergoing MRIs PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Evidence of bleeding diathesis or use of anticoagulant medication or any medication that may increase the risk of bleeding that cannot be stopped prior to surgery PHASE I: Tumor localized primarily to the posterior fossa or spinal cord PHASE I: Has known gliomatous meningitis, subependymal spread, or extracranial disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (temozolomide, CMV-specific T cells, surgery)<br>Patients receive temozolomide PO QD on days 1-21 and CMV-specific T cell transfer IV over 1-5 minutes on day 22. Patients undergo surgery on day 30 of cycle 1. Treatment repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive temozolomide PO QD on days 1-21. Treatment repeats every 42 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. | Biological: Autologous Cytomegalovirus-specific Cytotoxic T-lymphocytes<br>* Given IV<br>* Other names: Autologous CMV-specific CTLs;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|
| Active Comparator: Arm II (temozolomide, CMV-specific T cells)<br>Patients receive temozolomide PO QD on days 1-21 and CMV-specific T cell transfer intravenously IV over 1-5 minutes on day 22. Treatment repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. | Biological: Autologous Cytomegalovirus-specific Cytotoxic T-lymphocytes<br>* Given IV<br>* Other names: Autologous CMV-specific CTLs;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) (Recurrent Glioblastoma Participant Cohort)- Phase I | The number of participants who were treated at the respective dose level without DLT | Up to 42 days | 
| Number of Participants With Immunological Effects in Tumor Tissue (Recurrent Glioblastoma Cohort)- Phase II | Descriptive statistics will be used to summarize immunological effect. To evaluate the tumor-mediated immune suppression at the effector location, the markers (interferon, interleukin-2, and tumor necrosis factor alpha, perforin, granzyme B) will be measured for immune responses in the tumor microenvironment rather than in the peripheral blood. | Up to 4 years | 
| Progression Free Survival (PFS) (Recurrent Glioblastoma Cohort) at 6 Months- Phase II | Progression-free survival (PFS) is defined as the time from study enrollment until the time of first disease progression, relapse, or death due to disease. Patients who are alive without progression or relapse will be censored at the time of last contact. The point estimate of 6-month progression-free survival (PFS6) will be analyzed. Kaplan-Meier curves will be generated and median survival time will be derived. | 6 months | 
| Overall Survival (OS) (Newly Diagnosed Glioblastoma Cohort)- Phase II | Overall Survival is defined as the time from definitive histological diagnosis until the time of death. | Time from definitive histological diagnosis until death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (Recurrent Glioblastoma Cohort)- Phase II | The length of time from the date of diagnosis or the start of treatment for a disease until the disease starts to get worse or spread to other parts of the body. | Baseline to disease progression, assessed up to 4 years | 
| Overall Objective Response Rate (ORR) (Newly Diagnosed Glioblastoma Cohort)- Phase II | The number of participants with stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). | Up to 4 years | 
| Median Duration of Response (Newly Diagnosed Glioblastoma Cohort)- Phase II | Cox proportional hazard regression will be employed for multivariate analysis. | Baseline to response, assessed up to 4 years | 
| Progression Free Survival (PFS) (Newly Diagnosed Glioblastoma Cohort)- Phase II | Progression free survival is defined as time in weeks from start of study treatment to first documentation of objective tumor progression or up to death due to any cause, whichever occurs first. | At 6 months |