A Phase 1 Study of SAHA (NSC# 701852) 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
A Phase 1 Study of SAHA (NSC# 701852) 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
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. 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.
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose (MTD) of vorinostat (SAHA) in young patients with recurrent or refractory solid tumors or lymphomas.
II. 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.
III. Determine the tolerability of the solid tumor MTD of SAHA in young patients with recurrent or refractory leukemia.
IV. Determine the toxic effects of SAHA administered with or without isotretinoin in these patients.
V. Determine the pharmacokinetics of this drug in these patients.
SECONDARY OBJECTIVES:
I. Determine, preliminarily, the antitumor activity of SAHA administered with or without isotretinoin in these patients.
II. 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.
Inclusion Criteria:
Histologically confirmed* diagnosis of 1 of the following:
Recurrent or refractory solid tumor or lymphoma (for patients in group 1)
Recurrent or refractory leukemia (for patients in group 2)
Recurrent or refractory CNS tumor of 1 of the following types (for patients in group 3):
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
Performance status - Lansky 50-100% (for patients ≤ 10 years of age)
Performance status - Karnofsky 60-100% (for patients > 10 years of age)
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)
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
ALT ≤ 5 times ULN
Albumin ≥ 2 g/dL
Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min
Creatinine based on age as follows:
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)
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)
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 other concurrent biologic therapy or immunotherapy
More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) and recovered
No concurrent chemotherapy
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
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
At least 2 weeks since prior valproic acid
No other concurrent investigational agents
No other concurrent anticancer therapy
No concurrent enzyme-inducing anticonvulsants