Inclusion Criteria:
1. Age:
All subjects: Must be a maximum of 21 years of age at diagnosis. Age at enrollment by Phase:
1. Phase I-AYA (adolescents and young adult) Cohort: ≥12 years of age at
enrollment.
2. Phase I-Pediatric Cohort: < 12 years of age at enrollment; may start only after
DSMB review confirms the RP2D from the AYA cohort. No subject < 12 years will
be treated at a dose level higher than the RP2D established in the Phase I-AYA
Cohort.
3. Phase II: ≤ 21 years of age at diagnosis (with possibly two different
age-specific RP2Ds).
2. Pathology. All subjects must have a confirmed pathologic diagnosis of tumor type (except for
DIPG):
- - Relapsed/refractory Neuroblastoma (NB)
- Relapsed/refractory Embryonal tumor with multilayer rosettes (ETMR)
- Relapsed/refractory Atypical teratoid rhabdoid tumor (ATRT)
- Newly diagnosed Diffuse Intrinsic Pontine Glioma (DIPG)- radiologic diagnosis
acceptable.
- - Relapsed/refractory Ewing Sarcoma (EWS)
- Relapsed/refractory Osteosarcoma (OST)
3.
Tumor assessment:
Disease staging must be performed at baseline during the 28 day screening period
prior to first dose of study drug.
4. Disease Status:
Relapsed or Refractory Neuroblastoma Relapsed disease defined as: High-risk
neuroblastoma that was previously in remission after standard therapy (at least 4
cycles of aggressive multi-drug induction chemotherapy, with or without radiation,
surgery, and immunotherapy, or according to a standard high-risk
treatment/neuroblastoma protocol).
Refractory disease defined as: High-risk neuroblastoma that 1) failed to achieve CR
after at least 4 cycles of aggressive multi-drug induction chemotherapy with or
without radiation and surgery, followed by immunotherapy, or according to a standard
high-risk treatment/neuroblastoma protocol, or 2) progression during upfront therapy
or 3) with disease remaining after standard immunotherapy.
Eligible NB subjects may have active disease or no active disease.
NB Subjects with no active disease need to meet the following criteria:
Timing from prior therapy: Enrollment (first dose of study drug) no later than 60
days from most recent therapy.
NB Subjects with active disease need to meet the following criteria:
- - Received at least one recent treatment for their relapse/refractory disease and
is stable (SD) or better on this treatment.
*Stable disease defined as non-progression over 2 separate imaging studies at
least 6 weeks apart.
- - Subjects must not have disease in any organs (including lungs, liver, or
brain).
- - Measurable tumor size is < 2 cm.
- - Bone marrow < 40% involvement.
Relapsed or refractory ETMR/ATRT Subjects that have relapsed following standard of
care therapy or having progressed during standard of care therapy and
non-responsive/progressive to accepted curative therapy, including up-front
chemotherapy and radiation and/or high-dose chemotherapy with stem cell rescue.
ETMR/ATRT Subjects with no active disease need to meet the following criteria:
Timing from prior therapy: Enrollment (first dose of study drug) no later than 60
days from most recent therapy.
ETMR/ATRT Subjects with active disease need to meet the following criteria:
• Received at least one recent treatment for their relapse/refractory disease and is
stable (SD) or better on this treatment.
*Stable disease defined as non-progression over 2 separate imaging studies at least
6 weeks apart. Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) Subjects with DIPG to start
greater than 30 days, and no longer than 60 days, after standard of care radiation
therapy.
Subjects with newly-diagnosed typical DIPG, defined as tumors with a pontine
epicenter and diffuse involvement of the pons on at least 1 axial T2-weighted image,
are eligible. No histologic confirmation is required. Subjects with metastatic
disease are not eligible. Subjects with a biopsy and no evidence of H3K27m mutations
are eligible as long as they meet radiographic criteria. Subjects with H3K27m
altered DMG outside of the brainstem are not eligible. Subjects with progression or
recurrence after initial standard of care radiation are ineligible.
Relapsed or refractory Ewing sarcoma and osteosarcoma Subjects that have relapsed
following standard of care therapy or having progressed during standard of care
therapy. Standard of care therapy for Ewing sarcoma and osteosarcoma includes
multi-agent chemotherapy with local control consisting of either surgery or
radiation therapy.
EWS/OST Subjects with no active disease need to meet the following criteria:
Timing from prior therapy: Enrollment (first dose of study drug) no later than 60
days from most recent therapy.
EWS/OST Subjects with active disease need to meet the following criteria:
• Received at least one recent treatment for their relapse/refractory disease and is
stable (SD) or better on this treatment.
*Stable disease defined as non-progression over 2 separate imaging studies at least
6 weeks apart. 5. Subjects must be able to swallow capsules.
6. Subjects with CNS disease currently taking steroids must have been on a stable dose
of steroids for at least one week and must not have progressive hydrocephalus at
enrollment.
7. Subjects must have fully recovered from the acute toxic effects of all prior anti-
cancer chemotherapy and be within the following timelines:
1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of
enrollment onto this study (6 weeks if prior nitrosourea).
2. Small Molecule Inhibitor (anti-neoplastic agent): At least 7 days since the
completion of therapy with a small molecule inhibitor. For agents that have
known adverse events occurring beyond 7 days after administration, this period
must be extended beyond the time during which adverse events are known to
occur. The duration of this interval must be discussed with the Study Chair.
3. Immunotherapy: At least 4 weeks since the completion of any type of
immunotherapy, e.g. tumor vaccines, CAR-T cells except for anti-GD2 Monoclonal
antibodies (ex. naxitamab, dinutuximab, etc.) which should be at least 2 weeks
since prior treatment with a monoclonal antibody.
4. XRT: At least 14 days since the last treatment except for radiation delivered
with palliative intent to a non-target site.
Note: Subjects with DIPG will be required to have had up front standard of care
radiation. As above, subjects with DIPG must be between 30-60 days post initial
up front radiation therapy.
5. Stem Cell Transplant:
1. Allogeneic: No evidence of active graft vs. host disease. 2. Allo/Auto: ≥ 45 days must have elapsed since transplant.
6. MIBG Therapy: At least 6 weeks since treatment with MIBG therapy.
8. Subjects must have a Lansky or Karnofsky Performance Scale score of >/= 60. 9. Subjects must have adequate organ function at the time of enrollment:
- - Hematological: Hematological recovery as defined by ANC ≥750/μL (unsupported-
>24 hrs off G-CSF and 7 days off neulasta)
- Liver: Adequate liver function as defined by AST and ALT <10x upper limit of
normal.
- - Cardiac: all subjects must have:
1.
Normal serum Cardiac Troponin Concentration. 2. Normal BNP (B-type natriuretic peptide) Level. 3. A QTcF ≤ 470 msec (or EKG with no significant findings)
4. Normal ECHO defined as:
i. Shortening fraction of ≥ 27% by echocardiogram, or ii. Ejection fraction of
≥ 50% by echocardiogram or radionuclide angiogram.
- - Renal: Subjects must have adequate renal function defined as:
1.
For subjects < 17 years old: estimated Glomerular Filtration rate (eGFR)
as calculated from the Bedside Schwartz equation (in units of mL/min/1.73
m2) or via radioisotope GFR of ≥ 70 mL/min/1.73 m2. The Bedside Schwartz
equation is: [(0.413) X (Height in cm)] / SCr. 2. For subjects ≥17 years old: estimated Glomerular Filtration rate (eGFR) as
calculated from the Cockcroft and Gault formula (in units of mL/min/1.73
m2) or via radioisotope GFR of ≥ 70 mL/min/1.73 m2. The Cockcroft and
Gault formula is: [(140-age) x (Wt in kg) x (0.85 if female)] / (72 x SCr)
3. OR a 24 hour urine Creatinine clearance ≥ 70 mL/min/1.73 m2. 10. Subjects of childbearing potential must have a negative pregnancy test. Subjects of
childbearing potential must agree to use an effective birth control method. Subjects
who are lactating must agree to stop breast-feeding.
11. Written informed consent in accordance with institutional and FDA guidelines must be
obtained from all subjects (or subjects' legal representative).
Exclusion Criteria:
1. BSA of <0.25 m2. 2. Investigational Drugs: Subjects who are currently receiving another investigational
drug are excluded from participation.
3. Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are
not eligible. Subjects must have fully recovered from the hematological and bone
marrow suppression effects of prior chemotherapy.
4. Infection: Subjects who have an uncontrolled infection are not eligible until the
infection is judged to be well controlled in the opinion of the investigator.
5. Subjects who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study, or in whom compliance is likely to be
suboptimal, should be excluded.
