Clinical trial NCT00275080: Vorinostat and 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Blastic Phase Chronic Myelogenous Leukemia
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Nodal Marginal Zone B-cell Lymphoma
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Acute Myeloid Leukemia
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Adult Diffuse Mixed Cell Lymphoma
Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
Recurrent Adult Immunoblastic Large Cell Lymphoma
Recurrent Adult Lymphoblastic Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Small Lymphocytic Lymphoma
Secondary Acute Myeloid Leukemia
Splenic Marginal Zone Lymphoma
Stage III Adult Burkitt Lymphoma
Stage III Adult Diffuse Large Cell Lymphoma
Stage III Adult Diffuse Mixed Cell Lymphoma
Stage III Adult Diffuse Small Cleaved Cell Lymphoma
Stage III Adult Immunoblastic Large Cell Lymphoma
Stage III Adult Lymphoblastic Lymphoma
Stage III Grade 1 Follicular Lymphoma
Stage III Grade 2 Follicular Lymphoma
Stage III Grade 3 Follicular Lymphoma
Stage III Mantle Cell Lymphoma
Stage III Marginal Zone Lymphoma
Stage III Small Lymphocytic Lymphoma
Stage IV Adult Burkitt Lymphoma
Stage IV Adult Diffuse Large Cell Lymphoma
Stage IV Adult Diffuse Mixed Cell Lymphoma
Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
Stage IV Adult Immunoblastic Large Cell Lymphoma
Stage IV Adult Lymphoblastic Lymphoma
Stage IV Grade 1 Follicular Lymphoma
Stage IV Grade 2 Follicular Lymphoma
Stage IV Grade 3 Follicular Lymphoma
Stage IV Mantle Cell Lymphoma
Stage IV Marginal Zone Lymphoma
Stage IV Small Lymphocytic Lymphoma
Unspecified Adult Solid Tumor, Protocol Specific
Untreated Adult Acute Lymphoblastic Leukemia
Untreated Adult Acute Myeloid Leukemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-01-11
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

  * May be treated with intrathecal cytarabine and/or methotrexate prior to and/or during the study
* No known brain metastases in patients with solid tumors or NHL
* ECOG performance status 0-2
* Karnofsky 60-100%
* Life expectancy \> 12 weeks for patients with solid tumors (including non-Hodgkin's lymphoma) and 6 weeks for patients with hematological malignancies
* Patients with solid tumors (including NHL) must also have normal marrow function as defined below:

  * Leukocytes ≥ 3,000/mm\^3
  * Absolute neutrophil count ≥ 1,500/mm\^3
  * Platelets ≥ 100,000/mm\^3
* Creatinine ≤ 150 μmol/L
* Creatinine clearance ≥ 60 mL/min
* Bilirubin normal
* AST/ALT ≤ 2.5 times upper limit of normal (ULN)
* Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control or abstinence) prior to study entry and for the duration of study participation
* Not pregnant or nursing
* Negative pregnancy test
* No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or other agents used in study
* Able to take oral medications
* Patients who have a clinical or radiological diagnosis of bowel obstruction are ineligible
* No ongoing or active infection
* No symptomatic congestive heart failure
* No unstable angina pectoris
* No cardiac arrhythmia
* No psychiatric illness/social situations that would limit compliance with study requirements
* No other uncontrolled intercurrent illness
* No limitation on the number or types of prior therapy
* At least 3 weeks since prior radiotherapy, chemotherapy (6 weeks for nitrosoureas or mitomycin C), or molecularly targeted agents

  * Exceptions may be made for low-dose, non-myelosuppressive radiotherapy
* At least 2 weeks since prior valproic acid or any other histone deacetylase inhibitor
* Must have recovered from prior therapy
* Patients with hematological malignancies may receive hydroxyurea until 24 hours prior to starting study medications
* Previous surgery is permitted provided that wound healing has occurred
* No prior decitabine
* No other concurrent investigational agents
* No other concurrent investigational or commercial agents or therapies administered with the intent to treat the patient's malignancy
* No HIV-positive patients receiving combination antiretroviral therapy
* No concurrent prophylactic hematopoietic growth factors (e.g. filgrastim \[G-CSF\], sargramostim \[GM-CSF\], thrombopoietin, or epoetin alfa)

  * Hematopoietic growth factors colony stimulating factors for the treatment of cytopenia may be permitted at the discretion of the principal investigator

Primary outcomes:
measure: Maximum tolerated dose and recommended phase II dose of vorinostat and decitabine
timeFrame: Course 1
Secondary outcomes:
measure: Minimal effective dose of vorinostat in combination with decitabine by bone marrow and/or peripheral blood (for leukemia)
timeFrame: Baseline and between days 3-10
measure: Pharmacokinetics of vorinostat in conjunction with decitabine
timeFrame: Days 1-15
measure: Antitumor activity
timeFrame: Every 4 weeks for leukemia and every 8 weeks for solid tumors or NHL
measure: Methylation status of gene promoter regions and gene expression
timeFrame: Baseline and between days 3-10
measure: Altered response of leukemic cells to PPAr and RAR ligands
timeFrame: Baseline and between days 3-8
Other outcomes:
Locations:
city: Hamilton
country: Canada
facility: Chedoke-McMaster Hospitals
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital Phase 2 Consortium
state: Ontario
city: Toronto
country: Canada
facility: University Health Network-Princess Margaret Hospital
state: Ontario
Study officials:
affiliation: Princess Margaret Hospital Phase 2 Consortium
name: Karen Yee
role: PRINCIPAL_INVESTIGATOR
References: