A Phase I/II Clinical Study of Vorinostat in Combination With Etoposide in Pediatric Patients < 21 Years at Diagnosis With Refractory Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- Vorinostat and Etoposide
- Conditions
- Solid Tumors
- Sponsor
- Memorial Sloan Kettering Cancer Center
- Enrollment
- 27
- Locations
- 11
- Primary Endpoint
- To Establish the Dose Limiting Toxicity (DLT)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
The purpose of this study is to find out how safe and effective treatment with a new combination of drugs, vorinostat and etoposide, is in treating cancer. The medication etoposide is a standard medication used in the treatment of cancer in children. Vorinostat is an experimental drug which targets a protein(s) that control the way cancer cells grow and divide. Vorinostat is approved by the FDA in adults with certain cancers but not approved yet in children.
There are two parts to this study. In the first part of this study, the phase I portion, a safe dose of the combination, vorinostat and etoposide. The goal of second part of this study, the phase II portion, is to see how effective the combination of vorinostat and etoposide is in treating cancer.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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 institutional standard.
Exclusion Criteria
- •A patient meeting any of the following criteria is not eligible to participate in this study:
- •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 in the phase I component only.
- •Patients who have undergone prior autologous stem cell transplantation or allogeneic transplantation.
- •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 analogs.
- •Patients with symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions is eligible.
Arms & Interventions
Vorinostat and Etoposide
This is a multi-center, open label, phase I/II trial of escalating doses of vorinostat in combination with etoposide.
Intervention: Vorinostat and Etoposide
Outcomes
Primary Outcomes
To Establish the Dose Limiting Toxicity (DLT)
Time Frame: Patients will be assessed in 3-week cycles.
of the novel combination vorinostat and etoposide in pediatric patients with refractory solid tumors including tumors of the central nervous system. The Toxicity will be evaluated according to NCI CTCAE Version 4.0.
To Establish the Maximum Tolerated Dose (MTD)
Time Frame: 1 year
of the novel combination vorinostat and etoposide in pediatric patients with refractory solid tumors including tumors of the central nervous system.
To Establish the Efficacy (CR (Complete Response) + PR (Partial Response) Rate)
Time Frame: 1 year
of the novel combination vorinostat and etoposide in pediatric patients with relapsed/refractory sarcoma. Evaluation for response will be determined by Revised RECIST guideline
Secondary Outcomes
- To Evaluate the Biologic Effects Using Histone Acetylation, Gene Expression Profiling, and Histone Phosphorylation Profiling.(2 years)
- To Evaluate the Efficacy (CR (Complete Response) + PR (Partial Response) Rate)(1 year)