Novel Gamma-Delta (γδ)T Cell Therapy for Treatment of Patients With Newly Diagnosed Glioblastoma

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Brief Title

Novel Gamma-Delta (γδ)T Cell Therapy for Treatment of Patients With Newly Diagnosed Glioblastoma

Official Title

A Phase I Study of Drug Resistant Immunotherapy (DRI) With Activated, Gene Modified γδ T Cells in Patients With Newly Diagnosed Glioblastoma Multiforme Receiving Maintenance Temozolomide Chemotherapy

Brief Summary

      This study is being conducted to find out if the safety and tolerability of an experimental
      cell therapy is safe to administer to patients with a newly diagnosed glioblastoma multiforme
      (GBM) in combination with temozolomide (TMZ).
    

Detailed Description

      The cell therapy that is being used in this study is called gene-modified gamma delta T cells
      or Drug Resistant Immunotherapy (DRI). Gamma delta T cells are a type of lymphocyte or white
      blood cell that may help the immune system to recognize and kill cancer cells. Some
      chemotherapy can kill these gamma delta T cells. For the cell therapy being used in this
      study, the genes or DNA within these gamma delta T cells are modified so they are resistant
      to or may not be affected by chemotherapy. The chemotherapy that is being used in this study
      is called temozolomide (TMZ) and can reduce the number of these gamma delta T cells or
      lymphocytes. This study will also find out if these modified gamma delta T cells (DRI) are
      unaffected by TMZ. The DRI is given in combination with a standard dose of TMZ and is
      administered into the brain where the tumor is located.

      After subjects are consented in Parts A and B of the study, approximately about 2 tablespoons
      of blood will be collected for tests that may provide additional information about subjects T
      cells and how they may respond to treatment.

      Part A Subjects will have a surgical procedure completed that will remove their tumor (called
      a surgical resection). They will have a Rickham catheter placed which is a device typically
      used to deliver chemotherapy into the brain. The infusion catheter will be placed first prior
      to the tumor resection. A sample of tumor tissue will be taken and examined to confirm the
      diagnosis of GBM. The diagnosis of GBM must be confirmed prior to beginning Part B.

      Part B After the surgical resection and on Study Day 1, subjects will return to the study
      doctor's office/clinic to undergo a procedure called apheresis. This procedure will separate
      out cells called peripheral blood mononuclear cells (PBMC). Apheresis is the removal of blood
      plasma from the body by collecting your blood and separating the plasma from the PBMCs. These
      cells include the gamma delta T cells that will be used to synthesize the DRI γδ T cells.
      Once the cells for the DRI γδ T cells are synthesized, they are reintroduced into subject's
      brain through the Rickham catheter.

      Following apheresis and confirmation that the required number of gamma delta T cells were
      collected, subjects will begin the recommended or standard of care treatment for newly
      diagnosed GBM. This will include 6 weeks of chemotherapy with TMZ and radiation. Subjects
      will then have about 4 weeks of no treatment prior to beginning the Part B maintenance phase
      of treatment, which includes 6 cycles of TMZ. Depending on which dose level they receive,
      they will be administered either 1 injection of the DRI γδ T cells or 3 and these will be
      injected through the Rickham catheter.

      The first 3 subjects will receive a single dose of the DRI γδ T cells at the lowest dose
      level. Subjects receiving a single dose of the DRI γδ T cells will be observed for a of
      minimum 30 days from the time the first subject is enrolled, followed by a minimum of 7 days
      between each additional subject enrolled to allow for evaluation of potential side effects.
      If the DRI γδ T cell injection does not cause serious side effects, the second set of 3
      subjects will be enrolled. The second set of 3 patients will receive 3 doses of the DRI γδ T
      cells. The approximate duration of the study may be up to 15 years, or until disease
      progression or subjects withdraw from the study.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Primary: Highest safe dose frequency or maximally planned dose, if no dose-limiting toxicity observed.

Secondary Outcome

 Time to progression

Condition

Brain Tumor Adult

Intervention

DRI cell therapy

Study Arms / Comparison Groups

 DRI cell therapy
Description:  The only arm will receive the DRI modified gamma delta T cells following standard therapy with radiation and temozolomide chemotherapy concurrent.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

12

Start Date

February 11, 2020

Completion Date

January 2023

Primary Completion Date

January 2022

Eligibility Criteria

        Inclusion Criteria:

          -  Must have magnetic resonance imaging (MRI) features consistent with and suspicious for
             malignant glioma. This will be Part A - Tissue (biopsy) and Rickham catheter
             placement.

          -  Must have histologically or cytologically confirmed glioblastoma multiforme prior to
             administration of the DRI γδ T cell injection. This will be Part B - Screening and
             Study Treatment.

          -  Prior therapy: Must have completed a standard temozolomide and radiotherapy treatment
             as described in Part A and be eligible to receive maintenance therapy with
             temozolomide (consistent with NCCN guidelines for newly diagnosed GBM and maintenance
             therapy).

          -  Age ≥18 yearsΦ: Because no dosing or adverse event data are currently available on the
             use of γδ T cells in patients <18 years of age, children are excluded from this study
             but will be eligible for future pediatric Phase I single-agent trials.

          -  Karnofsky Performance Status ≥70%

          -  Life expectancy of greater than 12 weeks

          -  Patients must have organ and marrow function as defined below:

               1. leukocytes >3,000/µl

               2. absolute neutrophil count >1,500/µl

               3. Hgb greater than or equal to 9.0 g/dL

               4. platelets >100,000/µl

               5. total bilirubin within normal institutional limits

               6. AST (SGOT)/ALT (SGPT) <2.5 X institutional upper limit of normal

          -  Creatinine within normal institutional limits or if higher than the normal range,
             calculated creatinine clearance (CrCl) must be ≥ 50 mL/min/1.73 m2 (e.g., by
             Cockcroft-Gault formula); actual body weight must be used for CrCl unless body mass
             index (BMI) is > 30 kg/m2, in which case, lean body weight must be used

        Exclusion Criteria:

          -  Patients who have received any therapy for the treatment of GBM prior to inclusion in
             Part A and any treatment other than standard of care as described in Part A of this
             study including: cellular immunotherapy or gene therapy within 6 weeks prior to
             entering the study, surgical resection or alkylating agent chemotherapy within 4 weeks
             prior to entering the study, or have received experimental immunotherapy at any time,
             and those who have not recovered from adverse events due to therapeutic interventions
             administered more than 4 weeks earlier.

          -  Patients may not be receiving any other investigational agents.

          -  Contraindication to the placement of an intracranial access device (Rickham catheter)
             at the time of surgery.

          -  Prior history of encephalitis, multiple sclerosis, or other CNS infection

          -  Required steroid increase within 2 weeks of scheduled DRI γδ T cells administration.

          -  Uncontrolled intercurrent illness including, but not limited to ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or any othermedical condition that precludes surgery. Also, psychiatric
             illness/social situations that would limit compliance with study requirements.

          -  Allergies/hypersensitivity: Aminobisphosphonates such as Zoledronate®, Pamidronate® or
             similar

          -  Pregnant women are excluded from this study because the lentiviral- modified γδ T
             cells designed to express MGMT cells have an unknown potential for teratogenic or
             abortifacient effects. Because there is an unknown but potential risk for adverse
             events in nursing infants secondary to treatment of the mother with these cells,
             breastfeeding should be discontinued if the mother is treated with the
             lentiviral-modified γδ T cells designed to express MGMT. The following birth control
             methods are acceptable for this study in women of child- bearing potential:

          -  A Combination of TWO of the following:

               1. Barrier method of contraception:

                    1. condoms (male or female) with or without a spermicidal agent, diaphragm or
                       cervical cap with spermicide

                    2. IUD

               2. Hormone-based Contraceptive

          -  Note: Drug-drug interactions with some ARVs will make hormonal contraception a less
             reliable method.

          -  Because patients with immune deficiency will be unable to mount the anticipated immune
             response underlying this therapeutic rationale, HIV-seropositive patients are excluded
             from this study.

          -  Some of the contraceptive methods listed above may not prevent the spread of HIV to
             other people. Patients should discuss their contraceptive choices with their health
             care provider to choose the best way to both prevent pregnancy as required by this
             study and to prevent the spread of HIV to any partner(s).

          -  Patients with history of prior organ or bone marrow transplantation are not eligible.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Louis B Nabors, MD, 205-934-1432, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04165941

Organization ID

UAB 1773


Responsible Party

Principal Investigator

Study Sponsor

University of Alabama at Birmingham

Collaborators

 IN8bio, Inc.

Study Sponsor

Louis B Nabors, MD, Principal Investigator, University of Alabama at Birmingham


Verification Date

November 2019