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ADVL0416: A Phase 1 Study of SAHA 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

Date Last Modified: 09-07-2007
Date First Published: 02-10-2006

Basic Study Information

Type of TrialStatus of TrialAge Range (yrs.)Sponsor of TrialProtocol ID
Treatment Active 1-21 at study entry COG ADVL0416

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.
  • Group 4 (solid tumor or lymphoma patients): The pediatric suspension of SAHA will be administered once daily continuously at the MTD determined in group 1.  Therapy may continue as long as there is a response or a patient's disease remains stable.

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 at 1 month.

Objectives

Primary

  • To estimate the maximum tolerated dose (MTD) of SAHA administered once daily orally for 28 days to children with refractory or recurrent solid tumors.
  • To estimate the maximum tolerated dose (MTD) of SAHA administered once daily orally for 28 days in combination with 13-cis retinoic acid to children with refractory or recurrent neuroblastoma, medulloblastoma / CNS neuroectodermal tumor (PNET) or atypical teratoid rhabdoid tumor (ATRT).
  • To assess the tolerability of the solid tumor MTD in patients with recurrent or refractory leukemia.
  • To define and describe the toxicities of SAHA administered on this schedule as a single agent and in combination with 13 cis-retinoic acid.
  • To characterize the pharmacokinetics of SAHA given as a capsule and as a pediatric suspension in children with refractory cancer.

Secondary

  • To preliminarily define the antitumor activity of SAHA as a single agent and in combination with 13-cis retinoic acid within the confines of a Phase 1 study.
  • To assess the biologic activity of SAHA by measuring histone acetylation status in peripheral mononuclear cells (PMNC) and tumor tissue specimens.
  • To explore the effect of genetic polymorphisms (e.g., UGT1A1) on the pharmacokinetics of SAHA.

Projected Accrual

A maximum of 60 patients will be accrued for this study.

Mechanism of Action of SAHA

SAHA is a histone deacetylatase inhibitor that causes the arrest of cell cycle transition at G1 and G2M phase. It has been reported to selectively induce expression of p21 waf/CIP1 cyclin-dependent kinase inhibitor to effect cell cycle arrest1 and induces p53 independent apoptosis of U937 human leukemia cells. SAHA mediates the cleavage and activation of the pro-apoptotic Bcl-2 family member Bid, resulting in the release of cytochrome c and ROS from the mitochondria and cytosol. Although caspase activation is induced by SAHA, it is not necessary for SAHA induced cell death or cleavage of Bid. Ruefli et al has demonstrated that SAHA induced caspase activation is inhibited in P-gp expressing cells. SAHA inhibits partially purified HDACs 1 and 3 at concentrations as low as 100 nM and causes accumulation of acetylated histone in cells in culture at low micromolar concentrations. All 4 core nucleosomal histones (H2A, H2B, H3, and H4) become hyperacetylated following culture of transformed cells and normal cells with SAHA. In mice an increase in the accumulation of acetylated histones is detected in tumor xenografts following SAHA administration at doses that inhibit tumor growth.

SAHA binds to HDAC by inserting a hydroxamic group, most of the aliphatic chain and part of the phenyl amino group in the active site of the enzyme. The insertion of SAHA into the active site prevents the binding of the natural substrate and blocks enzymatic deacetylation.

A possible model for the antitumor action of SAHA is that SAHA inhibition of HDAC activity and subsequent accumulation of acetylated histones, leads to the activation of transcription of genes whose expression causes induction of differentiation or apoptosis and the inhibition of tumor growth. The expression of less than 2% of expressed genes is regulated following exposure to SAHA.

SAHA has also been shown to cross the blood brain barrier in an R6/2HD mouse model and increases histone acetylation in the brain.

Entry Criteria

  • Histologically confirmed* diagnosis of 1 of the following:
    • Recurrent or refractory solid tumor or lymphoma (for patients in group 1 and 4) 
    • 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, 3 and 4) 
      • No active CNS leukemia
      • Patients in group 4 of the study must agree to participate in the plasma pK studies during course 1.

          • 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 / mm3 (for solid tumor patients) 
          • Platelet count ≥ 100,000 / mm3* (for solid tumor patients) (20,000 / mm3** for leukemia patients) 
          • Hemoglobin ≥ 8.0 g/dL (RBC transfusion allowed) (for solid tumor and leukemia patients)
            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)

              Other

              • Not pregnant or nursing 
              • Negative pregnancy test 
              • Fertile patients must use effective contraception 
              • Body surface area ≥ 0.5 m2 
              • Neurologic deficits in patients with CNS tumors must be stable for ≥ 1 week before study entry 
              • Able to swallow whole capsules 
              • No uncontrolled infection

              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

              Who should I contact for more information?

              Rebecca Turner, CCRP
              Cincinnati Children's Hospital Medical Center
              Division of Hematology / Oncology
              3333 Burnet Ave.
              Cincinnati, OH 45229-3039
              Phone: 513-636-2799
              cancer@cchmc.org