Clinical Study of Vorinostat in Combination With Etoposide in Pediatric Patients < 21 Years at Diagnosis With Refractory Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Phoenix Children's Hospital
Milton S. Hershey Medical Center
Johns Hopkins University
Sidney Kimmel Comprehensive Cancer Center
Children's Hospital Colorado
University of Florida
Alberta Children's Hospital
M.D. Anderson Cancer Center
Dana-Farber Cancer Institute
Children's Mercy Hospital & Clinics
All Children’s Hospital Johns Hopkins Medicine
Arnold Palmer Hospital for Children/MD Anderson Cancer Center Orlando
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT01294670
First received: February 9, 2011
Last updated: April 3, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Solid Tumors
Relapsed/Refractory Sarcomas
Drug: Vorinostat and Etoposide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Clinical Study of Vorinostat in Combination With Etoposide in Pediatric Patients < 21 Years at Diagnosis With Refractory Solid Tumors

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • To establish the Dose Limiting Toxicity (DLT) [ Time Frame: Patients will be assessed in 3-week cycles. ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • To evaluate the efficacy (CR (complete response) + PR (partial response) rate) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    of the novel combination vorinostat and etoposide in pediatric patients enrolled in the phase I component of the study. Evaluation for response will be determined by Revised RECIST guideline.

  • To evaluate the biologic effects using Histone Acetylation, Gene Expression Profiling, and Histone Phosphorylation Profiling. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    of the novel combination of vorinostat and etoposide in pediatric patients with refractory solid tumors including central nervous system tumors


Estimated Enrollment: 50
Study Start Date: February 2011
Estimated Study Completion Date: February 2015
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vorinostat and Etoposide
This is a multi-center, open label, phase I/II trial of escalating doses of vorinostat in combination with etoposide.
Drug: Vorinostat and Etoposide
Patients will be assessed in 3-week cycles. Escalating doses of vorinostat will be administered orally on a daily x 4 schedule in combination with a fixed dose of etoposide. Etoposide will be administered intravenously daily x 3 days. Cohorts of 3-6 patients will be treated with vorinostat and etoposide. In the phase II component, patients will be treated at the RP2D established in the Phase I component of the study, which was found to be 270 mg/m2/dose of Vorinostat and 100 mg/m2/dose of Etoposide.

  Eligibility

Ages Eligible for Study:   4 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  • 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 irradiation.
  • Patient must be able to swallow capsules.
  • Patient must have an available archival/pre-treatment block or fresh tumor biopsy for molecular profiling to be performed.

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.
  • 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 abuse.
  • 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 patients, who are deemed low risk for recurrence by his/her treating physician are permitted to enroll.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01294670

Contacts
Contact: Tanya Trippett,, MD 212-639-8267
Contact: Christine Pratilas, MD 212-639-3964

Locations
United States, Arizona
Phoenix Children'S Hospital Not yet recruiting
Phoenix, Arizona, United States, 85016
Contact: Jessica Boklan, MD    602-546-0920      
Principal Investigator: Jessica Boklan, MD         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Lia Gore, MD    720-777-4159      
Principal Investigator: Lia Gore, MD         
United States, Florida
Arnold Palmer Hospital for Children/MD Anderson Cancer Center Orlando Recruiting
Orlando, Florida, United States, 32806
Contact: Amy Smith, MD    321-841-8588      
Principal Investigator: Amy Smith, MD         
All Children's Hospital Recruiting
St. Petersburg, Florida, United States, 33701
Contact: Gregory Hale, MD    727-767-4176      
Principal Investigator: Gregory Hale, MD         
United States, Maryland
John Hopkins Medical Center Not yet recruiting
Baltimore, Maryland, United States, 21287
Contact: Patrick Brown, MD    410-614-4915      
Principal Investigator: Patrick Brown, MD         
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Suzanne Shusterman, MD    617-632-4901      
Principal Investigator: Suzanne Shusterman, MD         
United States, Missouri
Children's Mercy Hospital & Clinics Recruiting
Kansas City, Missouri, United States, 64108
Contact: Kathleen Neville, MD    816-234-3059      
Principal Investigator: Kathleen Neville, MD         
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Tanya Trippett, MD    212-639-8267      
Contact: Christine Pratilas, MD    212-639-3964      
Principal Investigator: Tanya Trippett, MD         
United States, Pennsylvania
Pennsylvania State University College of Medicine Recruiting
Hershey, Pennsylvania, United States, 17110
Contact: Lisa McGregor, MD    717-531-6012      
Principal Investigator: Lisa McGregor, MD         
United States, Texas
Md Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Contact: Cynthia Herzog, MD         
Principal Investigator: Cynthia Herzog, MD         
Canada, Alberta
Alberta Children'S Hospital Not yet recruiting
Calgary, Alberta, Canada, T2N 1N4
Contact: Tony Truong, MD    403 955-2946      
Principal Investigator: Tony Truong, MD         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Merck Sharp & Dohme Corp.
Phoenix Children's Hospital
Milton S. Hershey Medical Center
Johns Hopkins University
Sidney Kimmel Comprehensive Cancer Center
Children's Hospital Colorado
University of Florida
Alberta Children's Hospital
M.D. Anderson Cancer Center
Dana-Farber Cancer Institute
Children's Mercy Hospital & Clinics
All Children’s Hospital Johns Hopkins Medicine
Arnold Palmer Hospital for Children/MD Anderson Cancer Center Orlando
Investigators
Principal Investigator: Tanya Trippett, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01294670     History of Changes
Other Study ID Numbers: 10-096
Study First Received: February 9, 2011
Last Updated: April 3, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Memorial Sloan-Kettering Cancer Center:
ETOPOSIDE (VP-16)
SAHA (SUBEROYLANILIDE HYDROXAMIC ACID) (Vorinostat)
Pediatric
10-096
POETIC
phase II component: the population will be restricted to relapsed/refractory sarcomas.

Additional relevant MeSH terms:
Neoplasms
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Etoposide
Etoposide phosphate
Vorinostat
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Histone Deacetylase Inhibitors

ClinicalTrials.gov processed this record on August 28, 2014