Description:
A Phase I open-label, multicenter study, to evaluate the safety, feasibility, and maximum
tolerated dose (MTD) of treating children with newly diagnosed DIPG or recurrent
neuroblastoma with molecular targeted therapy in combination with adoptive cell therapy
(Total tumor mRNA-pulsed autologous Dendritic Cells (DCs) (TTRNA-DCs), Tumor-specific ex vivo
expanded autologous lymphocyte transfer (TTRNA-xALT) and Autologous G-CSF mobilized
Hematopoietic Stem Cells (HSCs)).
Title
- Brief Title: Precision Medicine and Adoptive Cellular Therapy
- Official Title: Precision mEdicine and Adoptive Cellular tHerapy for the Treatment of Recurrent Neuroblastoma and Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG)
Clinical Trial IDs
- ORG STUDY ID:
BCC017
- NCT ID:
NCT04837547
Conditions
- Neuroblastoma
- Diffuse Intrinsic Pontine Glioma
Interventions
Drug | Synonyms | Arms |
---|
Tumor-specific ex vivo expanded autologous lymphocyte transfer (TTRNA-xALT) | xALT | Arm 1: Subjects with Diffuse Intrinsic Pontine Glioma (DIPG). |
Purpose
A Phase I open-label, multicenter study, to evaluate the safety, feasibility, and maximum
tolerated dose (MTD) of treating children with newly diagnosed DIPG or recurrent
neuroblastoma with molecular targeted therapy in combination with adoptive cell therapy
(Total tumor mRNA-pulsed autologous Dendritic Cells (DCs) (TTRNA-DCs), Tumor-specific ex vivo
expanded autologous lymphocyte transfer (TTRNA-xALT) and Autologous G-CSF mobilized
Hematopoietic Stem Cells (HSCs)).
Trial Arms
Name | Type | Description | Interventions |
---|
Arm 1: Subjects with Diffuse Intrinsic Pontine Glioma (DIPG). | Experimental | This Phase I study is will utilize a standard 3+3 dose escalation design to establish the MTD and will evaluate the following three pre-specified dose levels of xALT:
Dose Level 1: 3 x10^7 cells/kg Dose Level +1: 3 x10^8 cells/kg Dose Level -1: 3 x10^6 cells/kg
The dose escalation scheme will be evaluated for Arm 1 and Arm 2 separately. For each Study Arm, a minimum of 4 DLT evaluable subjects and a maximum of 12 DLT evaluable subjects will be enrolled (a total of 8 to 24 DLT evaluable subjects). | - Tumor-specific ex vivo expanded autologous lymphocyte transfer (TTRNA-xALT)
|
Arm 2: Relapsed/Refractory Neuroblastoma (NB) | Experimental | This Phase I study is will utilize a standard 3+3 dose escalation design to establish the MTD and will evaluate the following three pre-specified dose levels of xALT:
Dose Level 1: 3 x10^7 cells/kg Dose Level +1: 3 x10^8 cells/kg Dose Level -1: 3 x10^6 cells/kg
The dose escalation scheme will be evaluated for Arm 1 and Arm 2 separately. For each Study Arm, a minimum of 4 DLT evaluable subjects and a maximum of 12 DLT evaluable subjects will be enrolled (a total of 8 to 24 DLT evaluable subjects). | - Tumor-specific ex vivo expanded autologous lymphocyte transfer (TTRNA-xALT)
|
Eligibility Criteria
Inclusion Criteria:
- Subjects must have proven pediatric cancer with confirmation at diagnosis or at the
time of recurrence/progression and clinical determination of disease for which there
is no known effective curative therapy or disease that is refractory to established
proven therapies fitting into one of the following categories:
- Disease Status:
High Risk Neuroblastoma-
1. Patients that have relapsed following standard of care therapy or having progressed
during standard of care therapy and non-responsive/progressive to accepted curative
chemotherapy.
2. Neuroblastoma must be age >12 months at enrollment
Diffuse Intrinsic Pontine (or other brain stem) Glioma
1. Newly-diagnosed patients willing to undergo biopsy
2. Must be within 2 months of diagnosis and prior to starting radiation
3. DIPG must be ≥ 3 years of age at enrollment
- All subjects must be age ≤ 30 years at enrollment
- Patient and/or parents/guardian willing to consent to biopsy for obtaining tumor
material for confirmatory diagnosis and/or tumor RNA extraction and
amplification.
- Subjects must have measurable disease as defined Per section 8 at the time of
biopsy and tumor must be accessible for biopsy. Tumor samples submitted for
analysis must contain >30% viable tumor tissue to qualify. In addition, subjects
with NB disease confined to the bone marrow are eligible to enroll if the degree
of marrow involvement is expected to be >30%.
- Current disease state must be one for which there is currently no known effective
therapy
- Specimens will be obtained only in a non-significant risk manner and not solely
for the purpose of investigational testing.
- Lansky or Karnofsky Score must be ≥ 60
- Bone Marrow:
1. ANC (Absolute neutrophil count) ≥ 1000/µl (unsupported)
2. Platelets ≥ 100,000/µl (can be transfused)
3. Hemoglobin > 8 g/dL (can be transfused)
- Renal: Serum creatinine ≤ upper limit of institutional normal.
- Adequate liver function must be demonstrated, defined as:
1. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age AND
2. ALT (SGPT) ≤ 3 times upper limit of normal (ULN) for age
3. AST (SGOT) ≤ 3 times upper limit of normal (ULN) for age.
- Subjects with CNS disease currently taking steroids must have been on a stable
dose of steroids for at least one week prior to their biopsy and must not have
progressive hydrocephalus at enrollment.
- A negative serum pregnancy test is required for female participants of
childbearing potential (≥13 years of age or after onset of menses)
- Both male and female post-pubertal study subjects need to agree to use one of the
more effective birth control methods during treatment and for six months after
treatment is stopped. These methods include total abstinence (no sex), oral
contraceptives ("the pill"), an intrauterine device (IUD), levonorgestrel
implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera
shots). If one of these cannot be used, contraceptive foam with a condom is
recommended.
- Informed Consent: All subjects and/or legal guardians must sign informed written
consent. Assent, when appropriate, will be obtained according to institutional
guidelines
- Post-Biopsy: Patients with post-biopsy neurological deficits should have deficits
that are stable for a minimum of 1 week prior to registration.
Exclusion Criteria:
- Absence of tumor on biopsy specimen or a diagnosis other than NBL or glioma on biopsy
- Known autoimmune or immunosuppressive disease or human immunodeficiency virus
infection.
- Subjects with significant renal, cardiac, pulmonary, hepatic or other organ
dysfunction.
- Prior allergic reaction to GM-CSF or Td.
- Subjects who have received any cytotoxic chemotherapy within the last 7 days prior to
biopsy or focal radiotherapy in the case of patients with diffuse intrinsic pontine
(or other brain stem) gliomas
- Subjects with NBL who have received any radiotherapy to the primary sample site within
the last 14 days (radiation may be included in treatment decision after biopsy).
- Subjects receiving any investigational drug concurrently.
- Subjects with uncontrolled serious infections or a life-threatening illness (unrelated
to tumor)
- Subjects with any other medical condition, including malabsorption syndromes, mental
illness or substance abuse, deemed by the Investigator to be likely to interfere with
the interpretation of the results or which would interfere with a subject's ability to
sign or the legal guardian's ability to sign the informed consent, and subject's
ability to cooperate and participate in the study
Maximum Eligible Age: | 30 Years |
Minimum Eligible Age: | 1 Year |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Number of Participants with Dose Limiting Toxicities as a Measure of Safety and Tolerability |
Time Frame: | 2 years |
Safety Issue: | |
Description: | To evaluate the dose-limiting toxicities (DLTs) and to establish the maximum tolerated dose (MTD) of treating children with molecular targeted therapy in combination with adoptive cellular therapy |
Secondary Outcome Measures
Measure: | Number of Participants with Adverse Events as a Measure of Safety and Tolerability |
Time Frame: | 2 years plus 30 days |
Safety Issue: | |
Description: | To evaluate the overall safety profile of study treatment |
Measure: | Number of Participants that are able to have vaccine produced and delivered |
Time Frame: | 2 years |
Safety Issue: | |
Description: | To evaluable the feasibility of producing and administering the protocol directed therapy |
Measure: | Number of participants with progression free survival (PFS) during study |
Time Frame: | 7 years |
Safety Issue: | |
Description: | To determine the activity of treatments chosen based on Progression free survival (PFS) |
Measure: | Number of participants with overall survival (OS) during study |
Time Frame: | 7 years |
Safety Issue: | |
Description: | To determine the activity of treatments chosen based on Overall Survival (OS) |
Measure: | Determine the Overall Response Rate (ORR) of Participants using INSS Response Evaluation Criteria for NB and RANO criteria for DIPG |
Time Frame: | 2 years |
Safety Issue: | |
Description: | To determine the activity of treatments chosen based on Overall Response Rate (ORR) |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Giselle SaulnierSholler |
Last Updated
August 23, 2021