Purpose

This Phase I dose-escalation trial is designed to determine the safety and feasibility of rapidly generated tumor multi-antigen associated specific cytotoxic T lymphocytes (TAA-T) in patients with newly diagnosed diffuse intrinsic pontine gliomas DIPGs (Group A) or recurrent, progressive, or refractory non-brainstem CNS malignancies (Group B). Pediatric and adult patients who have high-risk CNS tumors with known positivity for one or more Tumor Associated Antigens (TAA) (WT1, PRAME and/or survivin) will be eligible to receive Tumor Antigen Associated Cytotoxic T Lymphocytes (TAA-T). Patients will be enrolled in one of two groups: Group A includes patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs) who will undergo irradiation as part of their upfront therapy and Group B includes patients with recurrent, progressive or refractory CNS tumors including medulloblastoma, non-brainstem high-grade glioma, and ependymoma, among others. TAA-T will be generated from patient's peripheral blood mononuclear cells (PBMCs) or by apheresis. This protocol is designed as a phase I dose-escalation study. Group A patients (DIPG patients): TAA-T will be infused any time > 2 week after completion of radiotherapy. Group B patients (other recurrent/progressive/refractory CNS tumors): TAA-T will be infused any time > 2 weeks after completing most recent course of conventional (non-investigational) therapy for their disease AND after appropriate washout periods as detailed in eligibility criteria.

Condition

Eligibility

Eligible Ages
Between 6 Months and 80 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

Recipient procurement inclusion criteria (Please see Appendix A1)

- Diagnosis of high-risk CNS tumors: DIPG, high-grade glioma, medulloblastoma, ependymoma, embryonal tumors, choroid plexus carcinoma, other aggressive CNS malignancies.

- Group A (newly diagnosed DIPG): planned completion of standard radiotherapy before receiving TAA-T therapy and radiographic diagnosis with DIPG defined as tumors with a pontine epicenter and diffuse intrinsic involvement of the pons

- Group B: Recurrent, progressive, or refractory disease after standard treatment. Refractory disease includes high-risk tumors with residual disease after completion of standard treatment.

- Measureable disease - patients must have measureable disease in 2-dimensions on MRI scan of the brain and/or spine.

- 6 months to 80 years of age at enrollment

- Karnofsky/Lansky score of ≥ 60% (see appendix B).

- Organ function:

- ANC >750/µL

- Platelets >75K

- Bilirubin <1.5x ULN

- AST/ALT < 5x ULN

- Serum creatinine <1.0mg/dL or 1.5x ULN for age (whichever is higher)

- Pulse oximetry > 90% on room air

- Agree to use contraceptive measures during study protocol participation (when age appropriate)

- Patient or parent/guardian capable of providing informed consent

- Available pre-trial tumor tissue (Group B)

Recipient procurement

Exclusion Criteria

  • Patients with uncontrolled infections
  • Patients with HIV infection
  • Pregnancy or lactating females
  • Prior immunotherapy with an investigational agent within the last 28 days prior to procurement
  • Patients with previous history of allogeneic stem cell transplantation (however, patients who have received autologous stem-cell infusions will remain eligible)
  • Bulky tumor
  • Group B - patients who have bulky tumor on imaging are ineligible. These include the following:
  • Tumor with any evidence of uncal herniation or significant midline shift
  • Tumor with a significant brainstem component
  • Patients who are deemed to have overly bulky tumor by the PI of the study

Exclusion Criteria:

Recipient inclusion criteria for initial TAA-T administration and for subsequent infusions (Please see Appendix A2)

- Steroids < 0.5 mg/m2 dexamethasone or equivalent per day

- Karnofsky/Lansky score of ≥ 60%

- Organ function:

- ANC >750/µL

- Platelets >75K

- Bilirubin <1.5x ULN

- AST/ALT < 5x ULN

- Serum creatinine <1.0mg/dL or 1.5x ULN for age (whichever is higher)

- Pulse oximetry > 90% on room air

- Patients must have received their last dose of known:

- Myelosuppressive chemotherapy (including completing radiotherapy for group A patients): ≥ 14 days prior to TAA-T infusion or demonstrated count recovery

- Investigational/biologic agent: seven days prior to TAA-T infusion. For agents that have known adverse events occurring beyond seven days after administration, this period must be extended beyond the time when new adverse events are known to commonly occur.

- Surgery: patients must have recovered from all acute effects of prior surgical intervention

- Neurologic status: Patients with neurologic deficits must have deficits that are stable for a minimum of 7 days prior to TAA-T infusions

Recipient exclusion criteria for initial and subsequent TAA-T infusions

- Patients with uncontrolled infections

- Bulky tumor

- Group B patients who have bulky tumor on imaging are not eligible to receive TAA-T infusion. These include the following:

- Tumor with evidence of uncal herniation or significant midline shift

- Tumor with a significant brainstem component

- Patients who are deemed to have overly bulky tumor by the PI of the study

- Patients who received ATG, Campath or other immunosuppressive T cell monoclonal antibodies within 28 days of TAA-T cell infusion.

- Pregnancy or lactating females

Study Design

Phase
Phase 1
Study Type
Interventional
Intervention Model
Single Group Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
TAA-T
Three different dosing schedules will be evaluated. Dose Level One: 2 x 107 cells/m2 Dose Level Two: 4 x 107 cells/m2 Dose Level Three: 8 x 107 cells/m2 Group A patients (DIPG patients): TAA-T will be infused any time > 14 days after completion of radiotherapy. Group B patients (other recurrent/progressive/refractory CNS tumors): TAA-T will be infused any time > 14 days after completing most recent course of conventional (non-investigational) therapy for their disease AND after appropriate washout periods as detailed in eligibility criteria. Ideally, patients should not receive other systemic antineoplastic agents for at least 45 days after the infusion of TAA-T, although such treatment may be added if deemed critical for patient care by the attending physician.
  • Biological: TAA-T
    Patients with newly diagnosed diffuse intrinsic pontine gliomas DIPGs (Group A) or recurrent, progressive, or refractory non-brainstem CNS malignancies (Group B). The goal of this cell infusion will be to initiate an immune response against brain tumors that includes multiple antigens and may prevent tumor evasion (through decreased expression of a single antigen)

Recruiting Locations

Children's National and nearby locations

Brain Tumor Institute, Children's National Medical Center
Washington, District of Columbia 20010
Contact:
Eugene Hwang, MD
202-476-5046
ehwang@childrensnational.org

More Details

NCT ID
NCT03652545
Status
Recruiting
Sponsor
Catherine Bollard

Study Contact

Eugene Hwang, MD
(202) 476 5046
EHwang@childrensnational.org

Detailed Description

This Phase I dose-escalation trial is designed to determine the safety and feasibility of rapidly generated tumor multi-antigen associated specific cytotoxic T lymphocytes (TAA-T) in patients with newly diagnosed diffuse intrinsic pontine gliomas DIPGs or recurrent, progressive, or refractory non-brainstem CNS malignancies. Patients who have high-risk CNS tumors with known positivity for one or more Tumor Associated Antigens (TAA) (WT1, PRAME and/or survivin) will be eligible to receive Tumor Antigen Associated Cytotoxic T Lymphocytes (TAA-T). Patients will be enrolled in one of two groups: Group A includes patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs) who will undergo irradiation as part of their upfront therapy and Group B includes patients with recurrent, progressive or refractory CNS tumors including medulloblastoma, non-brainstem high-grade glioma, and ependymoma, among others. TAA-T will be generated from patient's peripheral blood mononuclear cells (PBMCs) or by apheresis.

Group A patients (DIPG patients): TAA-T will be infused any time > 14 after completion of radiotherapy.

Group B patients (other recurrent/progressive/refractory CNS tumors): TAA-T will be infused any time > 14 after completing most recent course of conventional (non-investigational) therapy for their disease AND after appropriate washout periods as detailed in eligibility criteria.

This protocol is designed as a phase I dose-escalation study. In each treatment group (A and B), patients will be enrolled to one of the following TAA-T dose levels:

Dose Level 1 2 x 107 cells/m2 Dose Level 2 4 x 107 cells/m2 Dose Level 3 8 x 107 cells/m2

Two patients will be initially enrolled to the lowest dose level cohort (separately on each arm) and followed for 45 days after initial TAA-T for dose limiting toxicity (DLT) evaluations. The decision on whether it is safe to escalate to next dose level or not will be made after at least two patients in each dose level have finished their 45-days toxicity follow up after initial TAA-T. If the first two patients have not finished their 45 days follow-up, up to two additional incoming patients can be enrolled at the current dose level.

Two to four patients will be enrolled at each dose level (separately on each arm). Each patient will receive at least one TAA-T infusion and may receive a maximum of 8 doses if TAA-T is available. The first and second doses will be administered 45 days apart then additional doses will be spaced every 28 days. The expected volume of each infusion is 1 to 10 cc.

Group A and Group B patients will separately use the dose escalation strategy described above. Ideally, patients should not receive other systemic antineoplastic agents for at least 45 days after the infusion of TAA-T, although such treatment may be added if deemed critical for patient care by the attending physician.

If patients with measurable or evaluable disease have a response of stable disease or better by Response Assessment in Neuro-oncology (RANO) criteria at the day 28 evaluation after dose 2 or subsequent evaluations, they are eligible to receive up to 6 additional doses of TAA-T at 28 day intervals, if TAA-T supply allows. Each subsequent dose will be at the enrollment dose level (i.e. no subsequent dose escalation). The first and second doses will be administered 45 days apart then additional doses will be spaced every 28 days. Following dose number 1, if a patient's TAA-T supply is insufficient for subsequent doses at the enrollment dose level, further treatments may be administered at a lower dose level at the treating physician's discretion.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.