Protocol Summary

Protocol No.: OCR16024

Sponsor Protocol No.: UF-PED-001; BRAVO

Protocol Title.: Brain Stem Gliomas Treated With Adoptive Cellular Therapy During Focal Radiotherapy Recovery Alone or With Dose-intensified Temozolomide (Phase I)

Principal Investigator: Gururangan, Sridharan

Objective: The standard of care for children with DIPG includes focal radiotherapy (RT) but outcomes have remained dismal despite this treatment. The addition of oral Temozolomide (TMZ) concurrently with RT followed by monthly TMZ was also found to be safe but ineffective. Recent studies in adults have shown that certain types of chemotherapy induce a profound but transient lymphopenia (low blood lymphocytes) and vaccinating and/or the adoptive transfer of tumor-specific lymphocytes into the cancer patient during this lymphopenic state leads to dramatic T cell expansion and potent immunologic and clinical responses. Therefore, patients in this study will either receive concurrent TMZ during RT and immunotherapy during and after maintenance cycles of dose-intensive TMZ (Group A) or focal radiotherapy alone and immunotherapy without maintenance DI TMZ (Group B). Immune responses during cycles of DC vaccination with or without DI TMZ will be evaluated in both treatment groups.

Description: The standard of care for children with DIPG includes external beam focal radiotherapy (RT) but outcomes have remained dismal despite this treatment. The addition of oral Temozolomide (TMZ) concurrently with focal irradiation followed by maintenance monthly TMZ was also found to be safe but ineffective. However, in the context of an immunotherapy strategy, it might be beneficial to use TMZ as an adjuvant therapy during and following radiotherapy. Recent pre-clinical and clinical studies in adults with have shown that both myeloablative (MA) and non-myeloablative (NMA) chemotherapy induce a profound but transient lymphopenia and, somewhat counterintuitively, vaccination during recovery from this lymphopenic state and/or the adoptive transfer of tumor-specific lymphocytes into lymphodepleted hosts leads to dramatic in vivo T cell expansion and potent immunologic and clinical responses. Therefore, the study team expects that tumor-specific lymphocytes, expanded ex vivo with the use of TTRNA-pulsed DCs may provide a source of lymphocytes that preferentially expand in this lymphopenic environment following TMZ, and serve as a source of responder cells to subsequent DC vaccination. Although TMZ does induce profound lymphopenia in children with central nervous system (CNS) tumors, it has not been conclusively shown to help in augmenting vaccine-induced immune responses in this population. Therefore, patients in this study would either receive concurrent TMZ during RT and immunotherapy during and after maintenance cycles of dose-intensive TMZ (Group A) or focal radiotherapy alone and immunotherapy without maintenance DI TMZ (Group B). Immune responses during cycles of DC vaccination with or without DI TMZ will be evaluated in both treatment groups. The immunotherapy regimen will consist of TTRNA-DC vaccines alone followed by adoptive cellular therapy consisting of ex vivo expanded tumor-reactive lymphocytes coupled with TTRNA-DC vaccines and autologous HSCs. Patients in Group B will not receive DI TMZ, however, they will receive lymphodepletion with cyclophosphamide + fludarabine after DC vaccination and prior to the intravenous infusion of ex vivo expanded tumor-reactive lymphocytes, as T cell engraftment and persistence has been shown to be augmented by lymphodepletion in numerous studies. TTRNA-pulsed DCs will be given in conjunction with the adjuvants GM-CSF and tetanus-diphtheria toxoid (Td) vaccine which the study team have shown can significantly enhance clinical responses to DC vaccination.

Phase: Phase I

Age Group: Both

Age: 3 Years - 30 Years

Gender: All

Scope: Local

Treatment:
Group A
TTRNA-DC vaccines with GM-CSF and TTRNA-xALT plus Td vaccine with Autologous Hematopoietic Stem cells (HSCs) during cycles of Dose-intensified TMZ

Group B
TTRNA-DC vaccines with GM-CSF and TTRNA-xALT plus Td vaccine with Autologous Hematopoietic Stem cells (HSCs) with Cyclophosphamide + Fludarabine Lymphodepletive Conditioning

Detailed Eligibility:
INCLUSION CRITERIA:
Initial Screening:
1. Ages 3 to 21 years old
2. Radiologically confirmed DIPG and patient and/or parents/guardian willing to consent to biopsy;
3. Karnofsky Performance Status (KPS) of > 50% (KPS for > 16 years of age) or Lansky performance Score (LPS) of >= 50 (LPS for =< 16 years of age) assessed within 2 weeks prior to registration;
4. Bone Marrow
- ANC (absolute neutrophil count) >= 1000/µl (unsupported)
- Platelets >= 100,000/µl (unsupported)
- Hemoglobin > 8 g/dL (can be transfused)
5. Renal:
- Serum creatinine =< upper limit of institutional normal
6. Hepatic:
- Bilirubin =< 1.5 times upper limit of institutional normal for age
- SGPT (ALT) =< 3 times upper limit of institutional normal for age
- SGOT (AST) =< 3 times upper limit of institutional normal for age
7. Patients of childbearing or child-fathering potential must be willing to use medically acceptable forms of birth control while being treated on this study.
Post Biopsy:
1. Patients with post-surgical neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration;
2. Pathologic diagnosis of glioma on tumor biopsy.

EXCLUSION CRITERIA:
1. Patients with severe dysphagia, obtundation, or tetraplegia (poor risks for anesthesia and biopsy procedure);
2. Absence of tumor on biopsy specimen;
3. Pregnant or need to breast feed during the study period (Negative serum pregnancy test required)
4. Known autoimmune or immunosuppressive disease or human immunodeficiency virus infection;
5. Patients with significant renal, cardiac, pulmonary, hepatic or other organ dysfunction;
6. Severe or unstable concurrent medical conditions;
7. Patients who require corticosteroids above physiologic doses (>4 mg/day dexamethasone) after chemoradiotherapy;
8. Patients scheduled to receive any other concurrent anticancer or investigational drug therapy;
9 Prior allergic reaction to TMZ, GM-CSF, or Td;
10. Patients who are unwilling or unable to receive treatment and undergo follow-up evaluations at University of Florida;
11. Patient and/or parent/guardian demonstrating an inability to comply with the study and/or follow-up procedures.

Applicable Conditions:

  • Brain and Nervous System
  • Pediatric (Childhood) Cancer
  • Participation Institution:

  • UF Gainesville : Marcia Hodik
  • Contact:
    Marcia Hodik
    Phone: +1 352-273-6971
    Email: marcia.hodik@neurosurgery.ufl.edu

    More Information: View study listing on ClinicialTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03396575