A Phase I Clinical Trial With a Window-of-Opportunity Component of Engineered NK Cells Containing Deleted TGF-ßR2 and NR3C1 in Recurrent Grade 4 Astrocytoma (Glioblastoma)
Overview
- Phase
- Phase 1
- Intervention
- Cord Blood-derived Expanded Allogeneic Natural Killer Cells
- Conditions
- Recurrent Gliosarcoma
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 25
- Locations
- 1
- Primary Endpoint
- Incidence of dose-limiting toxicities (DLTs) (Group 1)
- Status
- Recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
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
PRIMARY OBJECTIVES: * To determine the safety and tolerability of intratumoral injection of escalating doses of allogeneic CB-NK-TGF-£\]R2-/NR3C1- in patients with recurrent grade 4 astrocytoma, * To determine the maximum tolerated dose (MTD) and the occurrence of dose limiting toxicities (DLTs) (Group 1) of CB-NK-TGF-£\]R2-/NR3C1- administered via IT injection in patients with recurrent grade 4 astrocytoma * To evaluate the immunological phenotype and anti-tumor function of NK cells in resected tumor tissue after treatment with CB-NK-TGF-âR2-/NR3C1- in the surgical expansion group (Group 2). Persistency of the NK cells in the tissue will be assessed by flow cytometry. Tissue cells will be stained with anti human CD45, anti human CD56 and anti HLA molecule expressed by the cord blood donor infused in the patient. NK cells from the tissue may be isolated using magnetic bead selection (anti-HLA specific from cord blood donor labeled with PE and them use a anti PE magnetics bead selection). Those NK cells would be used to perform a chromium release assay (killing assay) to test the ability of the NK in killing K562 and GSC targets. If the NK cells obtained from the tissue are too low to do killing assay, the NK cells could be expanded for one week using UAPC and IL2 to get more NK cells for assays. SECONDARY OBJECTIVE: -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)ƒn EXPLORATORY OBJECTIVES: -Monitoring immune responses following CB-NK-TGF-£\]R2-/NR3C1- dosing, in vivo persistence and expansion of CB-NK-TGF-£\]R2-/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-£\]R2-/NR3C1- trafficking in tumor microenvironments in the surgical expansion cohort. Tumor tissue from surgical resection will be further analyzed for immune infiltrates, fibrosis, and tumor microenvironment.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed and dated informed consent.
- •Male or female participants aged ≥ 12 years on the day of signing informed consent.
- •Has histologically confirmed supratentorial World Health Organization grade 4 recurrent astrocytoma to include recurrent IDH WT glioblastoma or gliosarcoma and recurrent IDHmutant 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. Lansky \>70 at trial entry for patients less than
- •Must be at least 12 weeks from receiving conformal radiation, unless RANO criteria for early progression are met.
- •A baseline brain MRI with Advance Brain Tumor Imaging (ABTI) 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.
- •Adequate hematological function defined by white blood cell (WBC) count ≥ 3 x 10°9/L with absolute neutrophil count (ANC) ≥ 1.5 x 10°9/L, lymphocyte count ≥ 0.5 x 10°9/L, platelet count ≥ 100 x 10°/L, and Hgb ≥ 9 g/ dL (in absence of blood transfusion).
- •Adequate hepatic function defined by a total bilirubin level ≤ 1.5 x ULN, an AST level ≤ 2.5 x ULN, and an ALT level ≤ 2.5 x 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 participant with creatinine levels \> 1.5 X institutional ULN
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 cancer directed investigational agent or using an investigational device within 4 weeks since last dose of agent administration or device use, 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
- •Note: Participants with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
- •Note: If participant 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.
Arms & Interventions
Group 1 (CB-NK-TGF-betaR2-/NR3C1- )
Participants will receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over additional 10 min via Ommaya catheter every four weeks for up to 8 doses in the absence of disease progression or unacceptable toxicity.
Intervention: Cord Blood-derived Expanded Allogeneic Natural Killer Cells
Group 2 (CB-NK-TGF-betaR2-/NR3C1-, resection)
Ommaya catheter will be inserted prior to the 1st injection of NK cells (at the time of screening biopsy). Two weeks prior to Surgical resection participants will receive the 1st dose of CB-NK-TGF-betaR2-/NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over an additional 10 min via Ommaya catheter. Ommaya catheter will be taken out at the time of standard of care surgical resection of the tumor on day 15 and then another one will be inserted at the end of surgery for future IT injections. Beginning 2 weeks after surgery, participants will receive CB-NK-TGF-betaR2-/ NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over additional 10 min via Ommaya catheter every 4 weeks for up to 7 doses (total of 8 doses) in the absence of disease progression or unacceptable toxicity.
Intervention: Cord Blood-derived Expanded Allogeneic Natural Killer Cells
Group 2 (CB-NK-TGF-betaR2-/NR3C1-, resection)
Ommaya catheter will be inserted prior to the 1st injection of NK cells (at the time of screening biopsy). Two weeks prior to Surgical resection participants will receive the 1st dose of CB-NK-TGF-betaR2-/NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over an additional 10 min via Ommaya catheter. Ommaya catheter will be taken out at the time of standard of care surgical resection of the tumor on day 15 and then another one will be inserted at the end of surgery for future IT injections. Beginning 2 weeks after surgery, participants will receive CB-NK-TGF-betaR2-/ NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over additional 10 min via Ommaya catheter every 4 weeks for up to 7 doses (total of 8 doses) in the absence of disease progression or unacceptable toxicity.
Intervention: Resection
Outcomes
Primary Outcomes
Incidence of dose-limiting toxicities (DLTs) (Group 1)
Time Frame: Up to 28 days
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.
Secondary Outcomes
- Overall survival (OS)(From definitive histological diagnosis until the time of death, assessed up to 90 days post-treatment)
- Objective response rate (ORR)(Up to 90 days post-treatment)
- Progression-free survival (PFS)(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)
- 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)(From the date of start of treatment until the tumor progression as defined by RANO, assessed up to 90 days post-treatment)