An open label, non-randomized study in pediatric patients with advanced high-grade gliomas
and other solid tumors.
The study will be performed in two phases: a dose escalation phase in up to 18 patients
following a standard "3+3" design to establish dose-limiting toxicity (DLT) and a "safe" dose
of 2-OHOA followed by an expanded safety cohort of up to 10 patients treated at the Maximum
Tolerated Dose (MTD). If the MTD is well tolerated in the expanded safety cohort, that dose
becomes the Recommended Phase 2 Dose (RP2D).
Glioma patients and other solid tumor patients (including non-glial brain tumors) will be
treated as a single cohort. Patients with either tumor type will be allowed to enroll on the
study as positions are made available. No tumor type will be given priority over another and
there is no minimum number of glioma patients or solid tumor patients that must be enrolled
on the trial.
The dose of 2-OHOA each patient will receive will depend on the dose cohort into which they
are enrolled.
Once a patient is allocated a dose of 2-OHOA (either in the dose escalation phase or the
expanded safety cohort), it is planned that they will continue to receive the same dose on a
daily basis in treatment cycles of 21 days (3 weeks), which may be repeated continuously
without therapy interruption, until any criterion for discontinuation is met (clinical or
radiological progression of disease, clinically unacceptable toxicity, or another "general"
discontinuation criterion is met as defined in Section 5.5). In the event of significant
gastrointestinal toxicity, the treatment schedule may be modified from continuous dosing to
an intermittent regime (e.g. 1 week of dosing followed by 1 week not dosing), except during
Cycle 1 of the dose escalation phase.
In the case of toxicity, the dose of 2-OHOA may be reduced or delayed by no more than 14 days
at the discretion of the Investigator. Treatment "holidays" of no more than 14 days are also
permitted for reasons other than toxicity, except during Cycle 1 of the dose escalation
phase.
Intra-patient dose escalation may be permitted in certain specific circumstances (and only if
≤ Grade 2 toxicity was observed during previous treatment cycles), but toxicity will not be
considered for definition of DLT.
It is expected that most patients will receive between one and 6 cycles of 2-OHOA for a
treatment period of 3 to 18 weeks. The treatment period may be extended provided that no DLT
has been observed and if in the opinion of the Investigator the patient is showing benefit
from treatment with 2-OHOA.
Patients demonstrating clinical benefit from 2-OHOA will have the option of continuing
treatment under compassionate use once the study has concluded.
Inclusion Criteria:
1. Age <18 years
2. Diagnosis: Patients must have a histologically- or cytologically-confirmed advanced
solid malignancy that is progressive, recurrent or refractory to standard-of-care
treatment, or for which there is no standard therapy.
3. Timing of therapy:
- Patients must be enrolled before treatment begins. Treatment must start within 14
days of study enrollment.
- All clinical and laboratory studies to determine eligibility must be performed
within 7 days prior to enrollment unless otherwise indicated in the eligibility
section.
4. Patients must have a Lansky or Karnofsky performance status score of ≥ 50%,
corresponding to ECOG categories of 0, 1 or 2. Use Karnofsky for patients > 16 years
of age and Lansky for patients ≤ 16 years of age. Patients who are unable to walk
because of paralysis, but who are up in a wheelchair will be considered ambulatory for
the purpose of assessing the performance score.
5. Able to swallow and ingest oral medication or have a NG or G-tube for drug
administration
6. Able to undergo adequate tumor imaging, via computerized tomography (CT) or magnetic
resonance imaging (MRI) scans or any other standardized tumor assessment method based
on tumor type (PET, MIBG, etc) to evaluate disease evolution
7. Adequate hematologic, renal, liver function as demonstrated by laboratory values:
- ANC ≥ 1,000/ul
- Hemoglobin ≥8.0 gm/dl
- Platelet count ≥ 100,000/ul
- Adequate Liver Function Defined As
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and
- SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age.
8. Adequate Renal Function Defined As Either
- Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73m2
- or a serum creatinine less than or equal to the institutional normal for age
9. No history of QTc prolongation, and a normal QTc interval at screening/baseline (QTc
≤450 msec)
10. No evidence of a bleeding diathesis
11. Negative pregnancy test in women of childbearing potential within 7 days of initiating
investigational therapy
12. Patient or legal guardian must give written, informed consent or assent (when
applicable) -
13. Recent mothers must agree not to breast feed while receiving medications on study.
Exclusion Criteria:
1. Age ≥ 18 years
2. Known hypersensitivity to any component of the study drug (see Section 6.1)
3. Use of any other investigational drug within five half-lives of that drug prior to the
first dose of 2-OHOA
4. Anti-cancer therapy within 4 weeks prior to the first dose of 2-OHOA (6 weeks for
mitomycin and nitrosureas, 4 weeks for curative-intent radiotherapy, and 2 weeks for
palliative radiotherapy)
5. Any National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE
version 4.0) >Grade 1 toxicities from prior chemotherapy or radiotherapy that could
impact on safety outcome assessment
6. Any surgery within 14 days prior to the first dose of 2-OHOA (excluding shunt or line
insertion)
7. Known >Grade 1 intracranial or intratumoral hemorrhage either by CT or MRI scan within
the last 1 month. Patients with resolving hemorrhage changes, punctuate hemorrhage or
hemosiderin may enter the study
8. A history of significant or uncontrolled cardiovascular disease, including New York
Heart Association Class III-IV heart failure, a left ventricular ejection fraction
which is clinically significantly abnormal as measured by 2-dimensional (2-D)
echocardiogram or Multi Gated Acquisition(MUGA) scan, unstable angina or myocardial
infarction within the preceding 6 months
9. Known impairment of gastrointestinal (GI) function that could alter the absorption of
study drug (e.g. active Crohn's disease, malabsorption syndrome or states, unresolved
diarrhea, small bowel resection or gastric by-pass surgery)
10. Patients who are unable to take oral medications because of significant uncontrolled
vomiting will be excluded.
11. A history of uncontrolled hyperlipidemia and/or the need for concurrent lipid lowering
therapy
12. Concurrent severe and/or uncontrolled other medical disease (e.g. uncontrolled
diabetes mellitus, active uncontrolled infection) that could compromise participation
in the study
13. Need for warfarin, phenytoin or sulphonylureas (glibenclamide, glimepiride,
glipizide,glyburide or nateglanide)
14. Any serious and/or unstable pre-existing medical, psychiatric or other condition which
in the Investigator's opinion could interfere with subject safety, obtaining written
informed consent, or compliance with the study protocol
15. Pregnant female patients are not eligible for this study. Pregnancy tests with a
negative result must be obtained in all post-menarchal females.
16. Lactating females must agree they will not breastfeed a child while on this study.
17. Males and females of reproductive potential may not participate unless they agree to
use an effective contraceptive method and continue to do so for at least 6 months
after the completion of therapy.
