A Phase 1 Study of Vorinostat (Suberoylanilide Hydroxamic Acid; SAHA) in Combination With Decitabine in Patients With Advanced Solid Tumors, Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia in Blast Crisis
Overview
- Phase
- Phase 1
- Intervention
- vorinostat
- Conditions
- Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 80
- Locations
- 4
- Primary Endpoint
- Maximum tolerated dose and recommended phase II dose of vorinostat and decitabine
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
This phase I trial is studying the side effects and best dose of vorinostat when given together with decitabine in treating patients with advanced solid tumors or relapsed or refractory non-Hodgkin's lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia.
Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving vorinostat together with decitabine may kill more cancer cells.
Detailed Description
PRIMARY OBJECTIVES: I. Establish the maximum tolerated dose and recommended phase II dose of vorinostat in conjunction with decitabine in patients with advanced solid tumors or relapsed or refractory non-Hodgkin's lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia in blast crisis. SECONDARY OBJECTIVES: I. Identify the minimal effective dose of vorinostat in conjunction with decitabine that will lead to DNA demethylation, histone acetylation, and gene reactivation with tolerable toxicity in these patients. II. Determine the pharmacokinetic profiles of vorinostat and decitabine in these patients. Correlate pharmacokinetic profiles of vorinostat and decitabine with toxicity and biological activity in these patients. III. Assess the antitumor activity of vorinostat and decitabine in these patients. OUTLINE: This is a parallel group, multicenter, dose-escalation study of vorinostat. Patients are stratified according to disease (solid tumors or non-Hodgkin's lymphoma \[NHL\] vs hematological malignancies). Patients receive 1 of 2 dosing regimens. Regimen 1 (sequential dosing): Patients receive oral vorinostat two or three times daily on days 6-21 or days 6-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Regimen 2 (concurrent dosing): Patients receive oral vorinostat two or three times daily on days 1-21, days 1-14 (patients with hematological malignancies only), or two times daily on days 1-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days 1-5. Courses repeat every 28 days or 21 days (patients with hematological malignancies only) in the absence of disease progression or unacceptable toxicity. In both groups, cohorts of 3-6 patients receive escalating doses of vorinostat 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. The dose level just below MTD would be declared the recommended phase II dose (RPTD). Up to 10 patients are treated at the RPTD. After completion of study treatment, patients are followed at 4 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Diagnosis of 1 of the following:
- •Confirmed relapsed or refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia in blast crisis (CML-BC)
- •Patients with acute promyelocytic leukemia who have relapsed while on tretinoin allowed
- •Patients with previously untreated AML who refuse induction chemotherapy allowed
- •Patients who are not candidates for aggressive management (those that have medical conditions that prevent the administration of standard curative chemotherapy or those who require an allogeneic bone marrow transplantation for curative therapy but lack an appropriate donor) are allowed
- •Histologically or cytologically confirmed relapsed or refractory non-Hodgkin's lymphoma (NHL)
- •Histologically confirmed solid tumor that is metastatic or unresectable or for which standard curative or palliative measures do not exist or are no longer effective
- •Clinically or radiologically documented disease
- •Patients whose only evidence of disease is tumor marker elevation are not eligible
- •Patients with AML, ALL, or CML-BC who have cerebral spinal fluid involvement may be included
Exclusion Criteria
- Not provided
Arms & Interventions
Treatment (enzyme inhibitor, chemotherapy)
Regimen 1 (sequential dosing): Patients receive oral vorinostat two or three times daily on days 6-21 or days 6-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Regimen 2 (concurrent dosing): Patients receive oral vorinostat two or three times daily on days 1-21, days 1-14 (patients with hematological malignancies only), or two times daily on days 1-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days 1-5.
Intervention: vorinostat
Treatment (enzyme inhibitor, chemotherapy)
Regimen 1 (sequential dosing): Patients receive oral vorinostat two or three times daily on days 6-21 or days 6-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Regimen 2 (concurrent dosing): Patients receive oral vorinostat two or three times daily on days 1-21, days 1-14 (patients with hematological malignancies only), or two times daily on days 1-12 (patients with solid tumors or NHL only) and decitabine IV over 1 hour on days 1-5.
Intervention: decitabine
Outcomes
Primary Outcomes
Maximum tolerated dose and recommended phase II dose of vorinostat and decitabine
Time Frame: Course 1
Graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Secondary Outcomes
- Minimal effective dose of vorinostat in combination with decitabine by bone marrow and/or peripheral blood (for leukemia)(Baseline and between days 3-10)
- Pharmacokinetics of vorinostat in conjunction with decitabine(Days 1-15)
- Antitumor activity(Every 4 weeks for leukemia and every 8 weeks for solid tumors or NHL)
- Methylation status of gene promoter regions and gene expression(Baseline and between days 3-10)
- Altered response of leukemic cells to PPAr and RAR ligands(Baseline and between days 3-8)