Engineered NK Cells Containing Deleted TGF-BetaR2 and NR3C1 for the Treatment of Recurrent Glioblastoma

Study Overview
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Brief Summary
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This phase I trial is to find out the best dose, possible benefits and/or side effects of engineered natural killer (NK) cells containing deleted TGF-betaR2 and NR3C1 (cord blood [CB]-NK-TGF-betaR2-/NR3C1-) in treating patients with glioblastoma that has come back (recurrent). CB-NK-TGF-betaR2-/NR3C1- cells are genetically changed immune cells that may help to control the disease.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the safety and tolerability of escalating doses of off-the-shelf CB-NK-TGF-betaR2-/NR3C1- in patients with recurrent glioblastoma (GBM), occurrence of dose limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD). (Group 1) II. To evaluate the immunological phenotype and anti-tumor function of NK cells in resected tumor tissue after treatment with CB-NK-TGF-betaR2-/NR3C1- in the surgical expansion group. (Group 2) SECONDARY OBJECTIVE: I. To determine response as measured by Response Assessment in Neuro-Oncology (RANO), duration of clinical response, progression free survival (PFS), time to progression (TTP), and overall survival (OS). EXPLORATORY OBJECTIVES: I. Monitoring immune responses following CB-NK-TGF-betaR2-/NR3C1- dosing, in vivo persistence and expansion of CB-NK-TGF-betaR2-/NR3C1- during treatment, characterization of immune cell subpopulations in the peripheral blood, serum analysis of immune correlates, alloreactivity characterization, and anti-HLA antibody analysis, and CB-NK-TGF-betaR2-/NR3C1- trafficking in tumor microenvironments in the surgical expansion cohort. II. Tumor tissue from surgical resection will be further analyzed for immune infiltrates, fibrosis, and tumor microenvironment. OUTLINE: This is a dose-escalation study followed by a dose-expansion study. Patients are assigned to 1 of 2 groups. GROUP 1: Patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes weekly for up to 8 doses in the absence of disease progression or unacceptable toxicity. GROUP 2: Patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes on days 0, 7, and 14. Patients undergo standard of care surgical resection on day 15. Beginning 2 weeks after surgery, patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes weekly for up to 5 doses (total of 8 doses) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 7, 30, and 90 days.

Official Title
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A Phase I Clinical Trial With a Window-of-Opportunity Component of Engineered NK Cells Containing Deleted TGF-ßR2 and NR3C1 in Recurrent Glioblastoma

Conditions
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Recurrent Gliosarcoma, Supratentorial Gliosarcoma, Recurrent Supratentorial Glioblastoma

Intervention / Treatment
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* Biological: Cord Blood-derived Expanded Allogeneic Natural Killer Cells
* Procedure: Resection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Signed and dated informed consent. Male or female subjects aged ≥ 18 years on the day of signing informed consent. Has histologically confirmed supratentorial World Health Organization grade 4 recurrent astrocytoma to include recurrent glioblastoma (IDH-wildtype grade 4 astrocytoma) recurrent IDH-mutant grade 4 astrocytoma, and recurrent gliosarcoma with any prior number of recurrences, and who have received prior radiation and temozolomide therapy. Participants will be eligible if the original histology was lower-grade glioma grade 2 or 3 and a subsequent histological diagnosis of recurrent glioblastoma or IDH-mutant grade 4 astrocytoma is made. Karnofsky Performance Score (KPS) of >70 at trial entry. Must be at least 12 weeks from receiving conformal radiation, unless RANO criteria for early progression are met. A baseline brain MRI must be obtained no more than 30 days prior to study registration Patients having undergone recent surgery are eligible so long as they are at least 3 weeks from resection or at least 1 week from stereotactic biopsy and recovered from any operative or perioperative complications. Patients with non-measurable tumor after resection will NOT be excluded; if they do not experience tumor progression while on trial, response will be labeled as stable disease (and not as complete response). Adequate hematological function defined by white blood cell (WBC) count ≥ 3 × 109/L with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, lymphocyte count ≥ 0.5 × 109/L, platelet count ≥ 100 × 109/L, and Hgb ≥ 9 g/ dL (in absence of blood transfusion). Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × ULN, an AST level ≤ 2.5 × ULN, and an ALT level ≤ 2.5 × ULN, and INR ≤ 1.5 Adequate renal function defined creatinine ≤1.5 X upper limit of normal (ULN) OR creatinine clearance ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Female subject of childbearing potential should have a negative serum pregnancy test within 14 days (+/-2 working days) of study registration. 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 and for 3 months after the last dose of study therapy. 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 2 methods of highly effective contraception starting with the first dose of study therapy and for 3 months after the last dose of study therapy. For the surgical expansion group (Group 2): there must be at least 1 cm2 of contrast-enhancing disease that is considered resectable by the neurosurgeon. Exclusion Criteria Has received prior therapy with Gliadel® or bevacizumab. Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics delivered by local injection or convection enhanced delivery. 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, or is planning to continue or start treatment with Optune® during participation in this trial. Has known severe hypersensitivity to monoclonal antibodies, any history of anaphylaxis, or recent, within 5 months, history of uncontrolled asthma. Has a known history of Human Immunodeficiency Virus (HIV) (positive HIV 1/2 antibodies); HTLV1 and/or HTLV2; active Hepatitis B (e.g., HbsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). Patients with prior HBV vaccination (anti-HBs positive, HbsAg negative, anti-HBc negative) will NOT be excluded. Has a diagnosis of immunodeficiency or is receiving any immunosuppressive therapy within 7 days prior to study registration. Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study Day 0. a. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. b. Note: If subject received major surgery (other than craniotomy), they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Has had prior radiation therapy less than 12 weeks prior to study registration, unless RANO criteria for early progression are met. Has had prior therapy with any antibody/drug targeting T cell co-regulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody within the last three months prior to study registration -. 10. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include but are not limited to basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. Any exceptions must be discussed with the protocol PI. Has known gliomatous cerebri, extracranial disease, or tumor localized primarily to the brainstem or spinal cord. Brain midline shift greater than 0.5 cm or pending herniation seen on baseline MRI. Tumors larger than 5 cm at greatest diameter 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 or that in the opinion of the PI may interfere with the subject's participation, assessment of experimental treatment toxicity or increase the subject's risk of side effects. 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, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit and through 3 months after last dose of the study treatment. Has received a live vaccine within 30 days prior to the first dose of trial treatment. Has a contraindication for undergoing MRIs. Has evidence of bleeding diathesis or coagulopathy. Is on full dose anticoagulants or antiplatelet therapy that cannot be held. Has significant hemorrhage on baseline MRI defined as >1 cm diameter of acute blood. Has received any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant). Has multifocal disease. Subject has multifocal GBM, defined as discrete sites of contrast enhancing disease without contiguous T2/FLAIR abnormality that require distinct radiotherapy ports. Satellite lesions that are associated with a contiguous area of T2/FLAIR abnormality as the main lesion(s) and that are encompassed within the same radiotherapy port as the main lesion(s) are permitted.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (CB-NK-TGF-betaR2-/NR3C1- )<br>Patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes weekly for up to 8 doses in the absence of disease progression or unacceptable toxicity. | Biological: Cord Blood-derived Expanded Allogeneic Natural Killer Cells<br>* Given CB-NK-TGF-betaR2-/NR3C1- intratumorally<br>* Other names: Umbilical Cord Blood-derived Expanded Allogeneic Natural Killer Cells;|
| Experimental: Group 2 (CB-NK-TGF-betaR2-/NR3C1-, resection)<br>Patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes on days 0, 7, and 14. Patients undergo standard of care surgical resection on day 15. Beginning 2 weeks after surgery, patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes weekly for up to 5 doses (total of 8 doses) in the absence of disease progression or unacceptable toxicity. | Biological: Cord Blood-derived Expanded Allogeneic Natural Killer Cells<br>* Given CB-NK-TGF-betaR2-/NR3C1- intratumorally<br>* Other names: Umbilical Cord Blood-derived Expanded Allogeneic Natural Killer Cells;Procedure: Resection<br>* Undergo surgical resection<br>* Other names: Surgical Resection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) (Group 1) | Will determine maximum tolerated dose and safety of escalating doses of cord blood (CB)-(NK) cells patients with recurrent glioblastoma. A DLT is defined as any grade >= 3 adverse event assessed as related to CB-NK cells by the investigator (that is, grade >= 3 adverse drug reaction; grading according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.03. | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS will be estimated using the Kaplan-Meier method and the comparison between or among patients' characteristics groups will be evaluated by log-rank test. Cox regression models will be applied to assess the effect of covariates of interest on OS. | From definitive histological diagnosis until the time of death, assessed up to 90 days post-treatment | 
| Objective response rate (ORR) | ORR will be defined as the proportion of patients with tumor size reduction (partial response and complete response, per Response Assessment in Neuro-Oncology [RANO] criteria). Will be calculated as the ratio of number of patients with response over number of patients treated, and 95% confidence interval of ORR will be estimated. | Up to 90 days post-treatment | 
| Duration of response (DOR) |  | From the time of initial response until documented tumor progression per RANO criteria, assessed up to 90 days | 
| Time to progression (TTP) | TTP will be estimated using the Kaplan-Meier method and the comparison between or among patients' characteristics groups will be evaluated by log-rank test. Cox regression models will be applied to assess the effect of covariates of interest on TTP. | From the date of start of treatment until the tumor progression as defined by RANO, assessed up to 90 days post-treatment | 
| Progression-free survival (PFS) | PFS will be estimated using the Kaplan-Meier method and the comparison between or among patients' characteristics groups will be evaluated by log-rank test. Cox regression models will be applied to assess the effect of covariates of interest on PFS. The point estimate of median PFS and 6-month progression-free survival (PFS6) will be estimated. | From the start of treatment until the time of first disease progression or relapse (as defined by RANO criteria), or death due to disease, assessed up to 6 months post-treatment |