A Phase I/II Clinical Study of Vorinostat in Combination With Etoposide in Pediatric Patients < 21 Years at Diagnosis With Refractory Solid Tumors
- Phase I Component: Histologic confirmation of relapsed/refractory solid tumors,
including tumors of the central nervous system that have failed to respond to
standard therapy, progressed despite standard therapy, or for which standard therapy
does not exist. Patients with diffuse pontine glioma are not required to have
histologic confirmation of disease, and are eligible with radiologic confirmation.
Phase II component: the population will be restricted to relapsed/refractory sarcomas
- Patient must be between 4-21 years of age at the time of study enrollment. Efforts
will be made to enroll patients <13 years of age so that adequate information about
the biologic effects of this agent in younger patients can be obtained.
- Patient must have Karnofsky > or = to 60% for patients >10 years of age; Lansky Play
Scale > or = to to 60 for children < or = to 10 years of age
- Patient must have a life expectancy of > 8 weeks.
- There is no limit to the number of prior treatment regimens provided that performance
status and life expectancy meet the criteria above.
- Absolute neutrophil count (ANC) ≥ 1000 / mcL
- Platelets ≥100,000 / mcL (transfusion not permitted)
- Hemoglobin ≥ 9 g/dL qualifications (transfusion permitted)
- Coagulation Prothrombin Time or INR ≤ 1.5x upper limit of normal (ULN)
- Serum creatinine ≤ 1.5x upper limit of normal (ULN) OR calculated creatinine
clearance ≥ 60 mL/min for patients with creatinine levels > 1.5x institutional ULN.
or calculated creatinine clearance Creatinine clearance should be calculated per
- Serum total bilirubin ≤ 1.5 x ULN Patient's who don't meet this criteria must have a
Direct bilirubin ≤ 1.5 x ULN
- AST (SGOT) and ALT (SGPT) Alkaline Phosphatase (liver fraction)
≤ 2.5 x ULN. If AST or ALT is > 2.5 x ULN, then the liver fraction of Alkaline
Phosphatase should be ≤ 2.5 x ULN
- Phase I component: Patients may have measurable or non-measurable disease. Phase II
component: Patients may only have measurable disease.
- Patient must have no persistent toxicities from prior therapy > or = to Grade 2 with
the exception of hematologic indices (i.e. hemoglobin, WBC, ANC, ALC).
- For females of childbearing potential, a negative serum pregnancy test must be
documented within 72 hours of receiving the first dose of vorinostat.
- Patient, or the patient's legal representative, has voluntarily agreed to participate
by giving written informed consent.
- Female patients of childbearing potential must be willing to use 2 adequate barrier
methods of contraception to prevent pregnancy or agree to abstain from heterosexual
activity throughout the study, starting with visit 1.
- Male patients must agree to use an adequate method of contraception for the duration
of the study.
- Prior Therapy: Patients must have fully recovered from the acute toxic effects of all
prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
- Myelosuppressive chemotherapy: At least 2 weeks must have elapsed since the
administration of previous therapy. Six weeks must have elapsed since administration
of nitrosoureas or mitomycin C. Seven days must have elapsed since the administration
of G-CSF and/or GM-CSF.
- Biologic agents: At least 14 days must have elapsed since the completion of therapy
with a biologic agent such as a monoclonal antibody. Seven days must have elapsed
since the last dose of retinoids.
- Radiation therapy (XRT): > or = to 2 weeks must have elapsed for local XRT (small
port); > or = to 6 months must have elapsed if prior radiation to > or = to 50% of
the pelvis or if other substantial bone marrow irradiation, including total body
- Patient must be able to swallow capsules.
- Patient must have an available archival or pre-treatment block for molecular
profiling to be performed(except for patient with a diagnosis of pontine glioma in
which a biopsy in unattainable).
- A patient meeting any of the following criteria is not eligible to participate in
- Patients currently participating or has participated in a study with an
investigational compound or device within 4 weeks of initial dosing with study drugs.
- Patients with a prior history of treatment with HDAC inhibitors ( e.g.
SNDX-275/entinostat, LAQ-824, LBH589, PXD-101/belinostat, etc). Patients who have
received Valproic acid will be excluded from this study.
- Patients with non CNS primary tumors who have known brain metastases or symptomatic
CNS disease (e.g. cranial nerve abnormalities) without cytologic abnormality in the
CSF should be excluded from this clinical trial because of their poor prognosis and
known propensity for the development of progressive neurologic dysfunction that would
confound the evaluation of neurologic and other adverse events. Patients with
metastatic CNS tumors will not be excluded from enrollment on this study.
- Patients who have undergone prior autologous stem cell transplantation or allogeneic
- Uncontrolled intercurrent illness or circumstances that could limit compliance with
the study requirements including, but not limited to: ongoing or active bacterial or
fungal infection, acute or chronic graft versus host disease, symptomatic congestive
heart failure, cardiac arrhythmia, or psychiatric illness/social situations.
- Patients who are pregnant or breastfeeding, or expecting to conceive within the
projected duration of the study. Because there is an unknown but potential risk for
adverse events in nursing infants secondary to treatment of the mother with
vorinostat, lactating patients will be excluded from this study.
- Patients known to be Human Immunodeficiency Virus (HIV)-positive.
- Patients with known hypersensitivity to the components of the study drugs or their
- Patients with symptomatic ascites or pleural effusion. A patient who is clinically
stable following treatment for these conditions is eligible.
- Patients who are at the time of signing informed consent, a regular user of any
illicit drugs, substance abuser or who have a recent history of drug or alcohol
- Patients with a known history of Hepatitis B or C.
- Patients who have a history of gastrointestinal surgery or other procedures that
might in the opinion of the investigator, interfere with the absorption or swallowing
of the study drug.
- Patients who are unable to take or tolerate oral medications on a continuous basis.
- Patients with a history of a prior malignancy who have undergone potentially curative
therapy with no evidence of that disease for five years, or who are deemed at low
risk for recurrence by his/her treating physician are permitted to enroll.