Vorinostat, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Lymphoma or Previously Untreated T-Cell Non-Hodgkin Lymphoma or Mantle Cell Lymphoma

Recurrent Mantle Cell Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00601718
• Other study ID #: PSOC 2302
• Secondary ID: NCI-2010-00870
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: January 24, 2008
• Last updated: September 2, 2014
• Start date: December 2007

Study information

• Verified date: September 2014
• Source: University of Washington
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

This phase I/II trial is studying the side effects and best dose of vorinostat when given together with rituximab, ifosfamide, carboplatin, and etoposide and to see how well they work in treating patients with relapsed or refractory lymphoma or previously untreated T-cell non-Hodgkin lymphoma or mantle cell lymphoma. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as ifosfamide, carboplatin, and etoposide, 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 rituximab and combination chemotherapy may kill more cancer cells

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. primary completion date: June 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• vorinostat
Given PO

Biological:
• rituximab
Given IV

Drug:
• ifosfamide
Given IV
• carboplatin
Given IV
• etoposide
Given IV

Other:
• pharmacological study
Correlative studies
• laboratory biomarker analysis
Correlative studies

Genetic:
• gene expression analysis
Correlative studies

Locations

Country	Name	City	State
United States	Puget Sound Oncology Consortium	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
University of Washington	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Budde LE, Zhang MM, Shustov AR, Pagel JM, Gooley TA, Oliveira GR, Chen TL, Knudsen NL, Roden JE, Kammerer BE, Frayo SL, Warr TA, Boyd TE, Press OW, Gopal AK. A phase I study of pulse high-dose vorinostat (V) plus rituximab (R), ifosphamide, carboplatin, and etoposide (ICE) in patients with relapsed lymphoma. Br J Haematol. 2013 Apr;161(2):183-91. doi: 10.1111/bjh.12230. Epub 2013 Jan 29. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose of vorinostat		28 days post last dose of study drug	Yes
Primary	Safety and toxicity according to CTCAE v3.0		3-5 weeks post end of treatment	Yes
Primary	Efficacy (response rate) of vorinostat combined with RICE chemotherapy		3-5 weeks post end of treatment	No
Primary	Ability to proceed to peripheral blood stem cell collection following treatment		1-3 weeks post end of treatment	No
Primary	Correlative studies		Baseline	No
Primary	Correlative studies		2 or 3 days before the start of chemotherapy	No