Vorinostat With or Without Isotretinoin in Treating Young Patients With Recurrent or Refractory Solid Tumors, Lymphoma, or Leukemia
Information source: National Cancer Institute (NCI)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Brain and Central Nervous System Tumors; Leukemia; Lymphoma; Neuroblastoma; Unspecified Childhood Solid Tumor, Protocol Specific
Intervention: isotretinoin (Drug); vorinostat (Drug)
Phase: Phase 1
Status: Active, not recruiting
Sponsored by: Children's Oncology Group Official(s) and/or principal investigator(s):
Maryam Fouladi, MD, Study Chair, Affiliation: St. Jude Children's Research Hospital
Julie R. Park, MD, Affiliation: Children's Hospital and Regional Medical Center, Seattle
Summary
RATIONALE: Drugs used in chemotherapy, such as vorinostat, work in different ways to stop the
growth of cancer cells, either by killing the cells or by stopping them from dividing.
Vorinostat may also stop the growth of cancer cells by blocking some of the enzymes needed
for cell growth and by blocking blood flow to the cancer. Isotretinoin may cause cancer cells
to look more like normal cells, and to grow and spread more slowly. Giving vorinostat
together with isotretinoin may be an effective treatment for cancer.
PURPOSE: This phase I trial is studying the side effects and best dose of vorinostat when
given together with isotretinoin in treating young patients with recurrent or refractory
solid tumors, lymphoma, or leukemia.
Clinical Details
Official title: A Phase I Study of SAHA (NSC#: 701852 IND#: 71976) in Pediatric Patients With Recurrent or Refractory Solid Tumors (Including Lymphomas) and Leukemia Followed By a Phase I Study of SAHA in Combination With 13-Cis-Retinoic Acid for Patients With Selected Recurrent/Refractory Solid Tumors
Study design: Treatment
Detailed description:
OBJECTIVES:
Primary
- Determine the maximum tolerated dose (MTD) of vorinostat (SAHA) in young patients with
recurrent or refractory solid tumors or lymphomas.
- Determine the MTD of SAHA administered in combination with isotretinoin in young
patients with recurrent or refractory neuroblastoma, medulloblastoma/CNS primitive
neuroectodermal tumor, or atypical teratoid rhabdoid tumor.
- Determine the tolerability of the solid tumor MTD of SAHA in young patients with
recurrent or refractory leukemia.
- Determine the toxic effects of SAHA administered with or without isotretinoin in these
patients.
- Determine the pharmacokinetics of this drug in these patients.
Secondary
- Determine, preliminarily, the antitumor activity of SAHA administered with or without
isotretinoin in these patients.
- Correlate the pharmacokinetics of this drug with genetic polymorphisms (e. g., UGT1A1) in
these patients.
OUTLINE: This is a multicenter, dose-escalation study of vorinostat (SAHA).
- Group 1 (solid tumor or lymphoma patients): Patients receive oral SAHA once daily on
days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of
disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose
(MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6
patients experience dose-limiting toxicity. An additional 6 patients may be treated at the
MTD.
- Group 2 (leukemia patients): Patients receive SAHA as in group 1 at the MTD.
- Group 3 (select solid tumor patients): Patients receive oral isotretinoin twice daily on
days 1-14. Patients also receive SAHA once daily on days 1-28 OR once on days 1, 3, 5,
8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 12
courses in the absence of disease progression or unacceptable toxicity.
The MTD of SAHA is determined as in group 1. An additional 6 patients may be treated at the
MTD.
After completion of study treatment, patients are followed periodically.
PROJECTED ACCRUAL: A maximum of 60 patients will be accrued for this study.
Eligibility
Minimum age: 1 Year.
Maximum age: 21 Years.
Gender(s): Both.
Criteria:
DISEASE CHARACTERISTICS:
- Histologically confirmed* diagnosis of 1 of the following:
- Recurrent or refractory solid tumor or lymphoma (for patients in group 1)
- Measurable or evaluable disease
- Recurrent or refractory leukemia (for patients in group 2)
- Greater than 25% blasts in the bone marrow (i. e., M3 bone marrow)
- Active extramedullary disease allowed except leptomeningeal disease
- Recurrent or refractory CNS tumor of 1 of the following types (for patients in
group 3):
- Neuroblastoma
- Medulloblastoma/CNS primitive neuroectodermal tumor
- Atypical teratoid rhabdoid tumor NOTE: *Histologic confirmation not required
for intrinsic brain stem tumors
- No known curative therapy or therapy proven to prolong survival with an acceptable
quality of life exists
- No bone marrow involvement by disease (for patients in groups 1 and 3)
- No active CNS leukemia
PATIENT CHARACTERISTICS:
Age
- 1 to 21
Performance status
- Lansky 50-100% (for patients ≤ 10 years of age)
- Karnofsky 60-100% (for patients > 10 years of age)
Life expectancy
- Not specified
Hematopoietic
- Absolute neutrophil count ≥ 1,000/mm^3 (for solid tumor patients)
- Platelet count ≥ 100,000/mm^3* (for solid tumor patients) (20,000/mm^3** for leukemia
patients)
- Hemoglobin ≥ 8. 0 g/dL (RBC transfusion allowed) (for solid tumor and leukemia
patients)
- Triglycerides < 300 mg/dL (for patients in group 3) NOTE: *Transfusion independent
NOTE: **Transfusion allowed
Hepatic
- Bilirubin ≤ 1. 5 times upper limit of normal (ULN)
- ALT ≤ 5 times ULN
- Albumin ≥ 2 g/dL
Renal
- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR
- Creatinine based on age as follows:
- No greater than 0. 8 mg/dL (for patients ≤ 5 years of age)
- No greater than 1. 0 mg/dL (for patients 6 to 10 years of age)
- No greater than 1. 2 mg/dL (for patients 11 to 15 years of age)
- No greater than 1. 5 mg/dL (for patients over 15 years of age)
- Negative dipstick for protein OR < 1,000 mg protein/24 hour urine collection (for
patients in group 3)
- No evidence of gross hematuria (for patients in group 3)
Other
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- Body surface area ≥ 0. 5 m^2
- Neurologic deficits in patients with CNS tumors must be stable for ≥ 1 week before
study entry
- Able to swallow whole capsules
- No uncontrolled infection
- Skin toxicity < grade 1 (for patients in group 3)
PRIOR CONCURRENT THERAPY:
Biologic therapy
- Recovered from prior immunotherapy
- At least 7 days since prior hematopoietic growth factors
- At least 7 days since prior antineoplastic biologic agents
- At least 2 months since prior stem cell transplantation or rescue
- No evidence of active graft-versus-host disease
- No other concurrent biologic therapy or immunotherapy
Chemotherapy
- More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas)
and recovered
- No concurrent chemotherapy
Endocrine therapy
- Patients with CNS tumors must be on a stable or decreasing dose of dexamethasone for ≥
7 days prior to study entry
- No concurrent dexamethasone for antinausea or antiemetic therapy
Radiotherapy
- Recovered from prior radiotherapy
- At least 2 weeks since prior local, palliative, small-port radiotherapy
- At least 3 months since prior total-body irradiation, radiotherapy to the craniospinal
area, or radiotherapy to ≥ 50% of the pelvis
- At least 6 weeks since other prior substantial radiotherapy to the bone marrow
- No concurrent radiotherapy
Surgery
- Not specified
Other
- At least 2 weeks since prior valproic acid
- No other concurrent investigational agents
- No other concurrent anticancer therapy
- No concurrent enzyme-inducing anticonvulsants
Locations and Contacts
Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham, Birmingham, Alabama 35294, United States
Children's Hospital of Orange County, Orange, California 92868, United States
Stanford Cancer Center, Stanford, California 94305-5824, United States
Children's National Medical Center, Washington, District of Columbia 20010-2970, United States
Children's Memorial Hospital - Chicago, Chicago, Illinois 60614, United States
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana 46202-5289, United States
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston, Massachusetts 02115, United States
C.S. Mott Children's Hospital at University of Michigan Medical Center, Ann Arbor, Michigan 48109-0286, United States
Mayo Clinic Cancer Center, Rochester, Minnesota 55905, United States
University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, United States
Siteman Cancer Center at Barnes-Jewish St. Peters Hospital - Saint Louis, St. Louis, Missouri 63110, United States
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, New York, New York 10032, United States
SUNY Upstate Medical University Hospital, Syracuse, New York 13210, United States
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, United States
Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
Oregon Health and Science University Cancer Institute, Portland, Oregon 97239-3098, United States
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-9786, United States
Hopital Sainte Justine, Montreal, Quebec H3T 1C5, Canada
St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States
Baylor University Medical Center - Houston, Houston, Texas 77030-2399, United States
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas, Dallas, Texas 75390, United States
Children's Hospital and Regional Medical Center - Seattle, Seattle, Washington 98105, United States
Additional Information
Clinical trial summary from the National Cancer Institute's PDQ® database
Starting date: August 2005
Last updated: May 23, 2008
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