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A Phase I/II Study of Vorinostat Plus Rituximab, Ifosphamide, Carboplatin, and Etoposide for Patients With Relapsed or Refractory Lymphoid Malignancies or Untreated T- or Mantle Cell Lymphoma


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Contiguous Stage II Mantle Cell Lymphoma, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Noncontiguous Stage II Mantle Cell Lymphoma, 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 Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin 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 Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Splenic Marginal Zone Lymphoma, Stage I Cutaneous T-cell Non-Hodgkin Lymphoma, Stage I Mantle Cell Lymphoma, Stage I Mycosis Fungoides/Sezary Syndrome, Stage II Cutaneous T-cell Non-Hodgkin Lymphoma, Stage II Mycosis Fungoides/Sezary Syndrome, Stage III Cutaneous T-cell Non-Hodgkin Lymphoma, Stage III Mantle Cell Lymphoma, Stage III Mycosis Fungoides/Sezary Syndrome, Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Mycosis Fungoides/Sezary Syndrome, Waldenström Macroglobulinemia

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Trial Information

A Phase I/II Study of Vorinostat Plus Rituximab, Ifosphamide, Carboplatin, and Etoposide for Patients With Relapsed or Refractory Lymphoid Malignancies or Untreated T- or Mantle Cell Lymphoma


OBJECTIVES:

I. To determine maximally tolerated dose of vorinostat that can be combined with RICE
chemotherapy in patients with relapsed lymphoid malignancies.

II. To determine the safety and toxicity of the above regimen. III. To gain a preliminary
assessment of the efficacy of the above regimen. IV. To determine the ability to proceed to
peripheral blood stem cell collection following the above regimens (the impact of above
regimen on stem cell reserve).

V. To describe vorinostat concentration attained at or near the MTD. VI. To evaluate the
change of histone acetylation patterns and pro-apoptotic proteins of primary target (tumor)
and non-target peripheral blood mononuclear cells (PBMC) cells following high-dose HDAC
inhibition.

VII. To describe the gene expression profile changes of tumor and non-tumor cells following
high-dose HDAC inhibition.

OUTLINE: This is a phase I/II dose-escalation study of vorinostat.

Patients receive vorinostat orally (PO) once daily (QD) on days 1-5, ifosfamide IV
continuously over 24 hours and carboplatin IV over 1 hour on day 4, and etoposide IV over 1
hour on days 3-5. Patients who are CD20+ also receive rituximab IV once on day 3, 4, or 5.
Treatment repeats every 21 days for 2 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and
then every 6 months for 4 years.


Inclusion Criteria:



- Patients must have relapsed or primary refractory lymphoid malignancy (including
B-cell, T-cell, or Hodgkins disease), or untreated T-NHL or MCL

- Patients with other lymphomas that have not received any prior therapy and are not
candidates for anthracycline-based therapies, are eligible with PI review and
approval

- Revised European American classification (REAL), or World Health Organization (WHO)
classification of patient's malignancies must be provided

- Patients must have measurable disease defined as lesions that can be accurately
measured in two dimensions by computed tomography (CT), magnetic resonance imaging
(MRI), medical photograph (skin or oral lesion), plain x-ray, or other conventional
technique and a greatest transverse diameter of 1 cm or greater; or palpable lesions
with both diameters >= 2 cm

- Patients must have a bone marrow aspirate and biopsy within 28 days of enrollment and
no intervening anticancer therapy

- Patients must have a CT of chest, abdomen, and pelvis within 28 days of enrollment;
patients with evidence of adenopathy in the neck must have a CT of neck

- Patients should not have evidence of active central nervous system lymphoma

- Electrocardiogram (EKG) must be free of any arrhythmias (excluding sinus arrhythmia
or infrequent premature ventricular contractions)

- Patients must have a Southwest Oncology Group (SWOG) performance status of 0, 1, or 2

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Serum creatinine < 1.5 mg/dl or creatinine clearance greater than 60/ ml per minute
by the following formula (all tests must be performed within 28 days prior to
registration)

- Total bilirubin < 1.5 times upper limit of normal, aspartate aminotransferase (AST) <
5 times upper limit of normal

- Patients must have a serum lactate dehydrogenase (LDH) performed within 14 days prior
to registration

- All patients must be informed of the investigational nature of this study and have
given written consent in accordance with institutional and federal guidelines

- Patients must be anticipated to complete at least 2 cycles of chemotherapy

- Platelets >= 100,000/mm^3 (without transfusion)

Exclusion Criteria:

- Patients known to be human immunodeficiency virus (HIV) positive

- Pregnant or nursing women; men or women of reproductive potential may not participate
unless they have agreed to use an effective contraceptive method

- Patients with other prior malignancies except for adequately treated basal cell
carcinoma, squamous cell carcinoma of the skin, cervical cancer in situ, or other
cancer from which the patient has been disease free for 5 years or greater, unless
approved by the protocol Chair or Co-Chair

- Patients that are refractory (i.e. not responded or progressed within 6 months) to a
carboplatin, cisplatin, ifosfamide, or etoposide-based regimen-based regimen

- Patients that have other medical conditions that would contraindicate treatment with
aggressive chemotherapy (including active infection, uncontrolled hypertension,
congestive heart failure, unstable angina pectoris, or myocardial infarction within
the past 6 months, or uncontrolled arrhythmia)

- Patients with a history of impaired cardiac status (including history of severe
coronary artery disease, cardiomyopathy, congestive heart failure or arrhythmia); if
the patient's history is questionable, a measurement of left ventricular ejection
fraction should be obtained within 42 days prior to registration; patients with left
ventricular ejection fraction < 50% are not eligible

- Autologous or allogeneic transplantation within 12 months or radioimmunotherapy
within 6 months of registration

- No concurrent treatment with valproic acid or on valproic acid within 2 weeks of
study enrollment

- No prior treatment with histone deacetylase inhibitors

- No concurrent therapy for this malignancy

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of vorinostat

Outcome Time Frame:

28 days post last dose of study drug

Safety Issue:

Yes

Principal Investigator

Lihua Budde

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Institutional Review Board

Study ID:

PSOC 2302

NCT ID:

NCT00601718

Start Date:

December 2007

Completion Date:

Related Keywords:

  • Adult Nasal Type Extranodal NK/T-cell Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Angioimmunoblastic T-cell Lymphoma
  • Contiguous Stage II Mantle Cell Lymphoma
  • Cutaneous B-cell Non-Hodgkin Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Nodal Marginal Zone B-cell Lymphoma
  • Noncontiguous Stage II Mantle Cell Lymphoma
  • 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 Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Cutaneous T-cell Non-Hodgkin 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 Mycosis Fungoides/Sezary Syndrome
  • Recurrent Small Lymphocytic Lymphoma
  • Splenic Marginal Zone Lymphoma
  • Stage I Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage I Mantle Cell Lymphoma
  • Stage I Mycosis Fungoides/Sezary Syndrome
  • Stage II Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage II Mycosis Fungoides/Sezary Syndrome
  • Stage III Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage III Mantle Cell Lymphoma
  • Stage III Mycosis Fungoides/Sezary Syndrome
  • Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage IV Mantle Cell Lymphoma
  • Stage IV Mycosis Fungoides/Sezary Syndrome
  • Waldenström Macroglobulinemia
  • Burkitt Lymphoma
  • Hodgkin Disease
  • Immunoblastic Lymphadenopathy
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Waldenstrom Macroglobulinemia
  • Mycoses
  • Mycosis Fungoides
  • Sezary Syndrome
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous
  • Lymphoma, Large-Cell, Anaplastic
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Extranodal NK-T-Cell
  • Lymphoma, Mantle-Cell

Name

Location

Puget Sound Oncology ConsortiumSeattle, Washington  98109