Clinical trial NCT03396575: Brain Stem Gliomas Treated With Adoptive Cellular Therapy During Focal Radiotherapy Recovery Alone or With Dose-intensified Temozolomide (Phase I)
Official title: BRAVO: Newly-Diagnosed Brain Stem Gliomas Treated With Adoptive Cellular Therapy During Recovery From Focal Radiotherapy Alone or Focal Radiotherapy and Dose-intensified Temozolomide (Phase I)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Diffuse Intrinsic Pontine Glioma (DIPG)
Brain Stem Glioma
Keywords: Tumor mRNA-pulsed autologous Dendritic Cells (TTRNA-DCs)
Tumor-specific autologous lymphocyte transfer (TTRNA-xALT)
Autologous G-CSF mobilized HSCs
Temozolomide (TMZ)
Cyclophosphamide (CTX)
Fludarabine (Flu)
Immunotherapy
Pediatric
Young Adult
Brain Tumor
CNS
Vaccine Therapy
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: Accelerate Brain Cancer Cure
name: Lyla Nsouli Foundation
First posted: 2018-01-11
Enrollment: 11
Sex: ALL
Minimum age (years): 3
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Patients in this study will either receive concurrent TMZ during RT and dose-intensive TMZ as maintenance treatment (Group A) or radiotherapy only prior to DC vaccination and 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.

Once Group A accrual is completed and evaluated for toxicity, 6 Group B patients will be enrolled and treated at the Maximally Achievable Dose (MAD) or (Maximum Tolerated Dose) MTD determined in Group A cohort.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

TMZ induces 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. 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. 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. 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.

Eligibility criteria: Inclusion Criteria:

Initial Screening

* Radiologically confirmed DIPG or other diffuse intrinsic brain stem glioma (Grade III or IV).
* Patient and/or parents/guardian willing to consent to biopsy for obtaining tumor material for confirmatory diagnosis and/or tumor RNA extraction and amplification.
* Biopsy confirmation of any grade of glioma (for patients with classic DIPG on neuroimaging or at least grade III glioma in case of other diffuse intrinsic brain stem gliomas)
* 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;
* Bone Marrow;
* ANC (absolute neutrophil count) ≥ 1000/µl (unsupported)
* Platelets ≥ 100,000/µl (unsupported)
* Hemoglobin \> 8 g/dL (can be transfused)
* Renal;
* Serum creatinine ≤ upper limit of institutional normal
* 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
* Patients of childbearing or child-fathering potential must be willing to use medically acceptable forms of birth control while being treated on this study.
* Signed informed consent according to institutional guidelines.

Post Biopsy

* Patients with post-surgical neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration;
* Pathologic diagnosis of glioma on tumor biopsy.

Exclusion Criteria:

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

Primary outcomes:
measure: Feasibility and safety of adoptive cellular therapy in pediatric patients with DIPG with or without dose-intensified TMZ during cycles of DC vaccination
timeFrame: From first DC Vaccine through 30 days after administration of the last dose of trial drug or subject death
measure: Determine the maximally achievable dose (MAD) or maximum tolerated dose (MTD) of xALT plus DC and HSC in Group A and Group B subjects
timeFrame: From first DC vaccine in Group A until 14 days after administration of the last dose of investigational product is given.
Secondary outcomes:
measure: Post-immunotherapy functional anti-tumor immune responses
timeFrame: Up to 10 months
measure: Analysis of progression-free survival (PFS)
timeFrame: Up to 5 years
measure: Analysis of overall survival (OS)
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: UF Health Shands Children's Hospital
state: Florida
Study officials:
affiliation: University of Florida
name: Elias Sayour, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: