Vorinostat, Rituximab, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II, Stage III, or Stage IV Diffuse Large B-Cell Lymphoma
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Purpose
This phase I/II trial is studying the side effects and best dose of vorinostat when given together with rituximab and combination chemotherapy and to see how well it works in treating patients with newly diagnosed stage II, stage III, or stage IV diffuse large B-cell lymphoma. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Monoclonal antibodies, such as rituximab, can block cancer cell 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 cell-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, 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
| Condition | Intervention | Phase |
|---|---|---|
|
Contiguous Stage II Adult Diffuse Large Cell Lymphoma Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma Stage III Adult Diffuse Large Cell Lymphoma Stage IV Adult Diffuse Large Cell Lymphoma |
Drug: doxorubicin hydrochloride Drug: vorinostat Other: diagnostic laboratory biomarker analysis Biological: rituximab Drug: cyclophosphamide Drug: prednisone Drug: vincristine sulfate |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | A Phase I/II Trial of Vorinostat (SAHA) (NSC-701852) in Combination With Rituximab-CHOP in Patients With Newly Diagnosed Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL) |
- Safe dose of vorinostat to be used in combination with R-CHOP assessed by CTCAE Version 4.0 (phase I) [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
- Progression-free survival (phase II) [ Time Frame: From date of registration to date of first observation of progressive disease or death due to any cause, up to 2 years ] [ Designated as safety issue: No ]
- Overall survival (phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
- Response rate (CR+PR) (phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 95 |
| Study Start Date: | November 2010 |
| Estimated Primary Completion Date: | December 2015 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Treatment (combination chemotherapy)
Patients receive vorinostat PO once daily on days 1-5 or 1-9 (according to dose level), rituximab IV, cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 3. Patients also receive prednisone PO once daily on days 3-7. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: vorinostat
Given PO
Other Names:
Other: diagnostic laboratory biomarker analysis
Correlative studies
Biological: rituximab
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: prednisone
Given IV
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
|
Detailed Description:
OBJECTIVES:
I. To find a safe dose of vorinostat to be used in combination with R-CHOP in patients with newly diagnosed stage II-IV diffuse large B-cell lymphoma. (Phase I) II. To estimate the 2-year progression-free survival (PFS) rate in patients treated with this regimen. (Phase II) III. To estimate the response rate (complete and partial) and 2-year overall survival rate. (Phase II) IV. To evaluate the toxicity of this regimen in these patients. (Phase II) V. To assess whether pre-treatment acetylation status of histones, expression of MHC Class II genes, and/or percentage of CD8+ tumor infiltrating lymphocytes correlate with PFS. (Phase II) VI. To explore whether treatment with vorinostat-R-CHOP increases histone acetylation, alters expression of MHC class II proteins, or alters percentage of T-cell subsets (CD8+, CD4+, FOXP3+) or infiltrating macrophages. (Phase II) VII. To explore whether histone acetylation status of tumor tissues correlates with MHC class II expression of peripheral blood B cells and lymphocyte subsets. (Phase II) VIII. To explore whether the change in systemic levels of immune cytokines with vorinostat-R-CHOP correlates with lymphoma symptoms, response, PFS, or overall survival. (Phase II)
OUTLINE: This is a multicenter, phase I dose escalation study of vorinostat followed by a phase II study.
Patients receive vorinostat orally (PO) once daily on days 1-5 or 1-9 (according to dose level), rituximab intravenously (IV), cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 3. Patients also receive prednisone PO once daily on days 3-7. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.
Paraffin block, core needle biopsy, and whole blood samples may be collected at baseline and during the first course of treatment for further analysis.
After completion of study treatment, patients are followed every 6 months for 2 years, and then annually for 3 years.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Biopsy-proven* newly diagnosed confirmed diffuse large B-cell lymphoma
- Stage II bulky, stage III, or stage IV disease
- Measurable disease by CT scan or PET/CT of the chest, abdomen, and pelvis within the past 28 days
- International Prognostic Index (IPI) or Revised-IPI score > 0
- CD20-positive disease
Adequate sections from the original diagnostic specimen available
- Fine needle aspiration or cytology is not adequate
- No clinical evidence of CNS involvement by lymphoma
- Zubrod performance status 0-2
- ANC > 1,000/mm^3 (unless due to bone marrow infiltration by lymphoma)
- Platelet count > 100,000/mm^3 (unless due to bone marrow infiltration by lymphoma)
- Serum lactate dehydrogenase measured within the past 28 days
- Cardiac ejection fraction normal by MUGA OR 2-dimensional ECHO (2-D ECHO)
- No significant cardiac abnormality by MUGA or 2-D ECHO
- Not pregnant or nursing
- Fertile patients must use effective contraception
- Willing to discontinue any medications that generally have a risk of causing Torsades de Pointes during study treatment
No other prior malignancy except for the following:
- Adequately treated basal cell or squamous cell skin cancer
- In situ cervical cancer
- Adequately treated stage I or II cancer from which the patient is currently in complete remission
- Any other cancer from which the patient has been disease-free for 5 years
- No known HIV positivity
- No known hypersensitivity to the components of study treatment
- No prior chemotherapy, radiotherapy, or antibody therapy for lymphoma (steroid pre-medication for IV contrast allergy allowed)
- More than 28 days since prior valproic acid (a histone deacetylase inhibitor)
Contacts and Locations
Show 176 Study Locations| Principal Investigator: | Daniel Persky | Southwest Oncology Group |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT00972478 History of Changes |
| Other Study ID Numbers: | NCI-2011-01964, S0806, U10CA032102 |
| Study First Received: | September 4, 2009 |
| Last Updated: | March 18, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Lymphoma Lymphoma, Non-Hodgkin Lymphoma, B-Cell Lymphoma, Large B-Cell, Diffuse Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Antibodies, Monoclonal Cyclophosphamide Rituximab Vorinostat Doxorubicin |
Prednisone Vincristine Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions Immunosuppressive Agents Antirheumatic Agents Therapeutic Uses Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists Antibiotics, Antineoplastic Glucocorticoids |
ClinicalTrials.gov processed this record on May 23, 2013