September 1, 2010
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September 2, 2010
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August 8, 2017
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October 6, 2010
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October 14, 2016 (Final data collection date for primary outcome measure)
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- Complete response rate assessed by Response Evaluation Criteria in Solid Tumors (Phase II) [ Time Frame: Up to 5 years ]
The difference between the complete response rate proportions (i.e., chemo alone vs. chemo + vorinostat) will be tested using the normal approximation for a two sample test of proportions.
- Incidence of adverse events (AEs) for each treatment arm assessed by CTCAE v4.0 (Phase II) [ Time Frame: Up to 5 years ]
The frequency of AEs and their severity will be tabulated for each treatment arm (i.e., chemo alone and chemo + vorinostat).
- Recommended phase II dose of vorinostat determined according to dose-limiting toxicities graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) (Phase I) [ Time Frame: 21 days ]
Toxicity data will be presented by severity for each dose group. The incidence of toxicity related dose reductions and treatment discontinuations will be summarized for each dose group. If there are a sufficient number of patients in each dose group, chi square analyses will be used to compare dose groups with respect to the incidence of specific toxicities.
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- Maximum-tolerated dose and recommended phase II dose of vorinostat and risk-adapted chemotherapy with rituximab (Phase I)
- Toxicity (Phase II)
- Complete response (Phase II)
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Complete list of historical versions of study NCT01193842 on ClinicalTrials.gov Archive Site
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- Change in CD8 cell counts (Phase I) [ Time Frame: Baseline up to 12 months ]
Evaluated using analyses of variance.
- Changes in CD4 cell counts (Phase I) [ Time Frame: Baseline up to 12 months ]
Evaluated using analyses of variance. For each dose group and for all groups combined, the Wilcoxon signed rank test will be used to evaluate the changes in HIV viral load and CD4 count. If there is sufficient number of patients in each dose group, the Kruskal-Wallis test will be used to compare dose groups with respect to changes in HIV viral load and CD4 count.
- Changes in Epstein-Barr virus (EBV) viral load [ Time Frame: Baseline up to 12 months ]
Descriptive statistics such as frequencies and percentages will be used to aid in the evaluation of EBV and human herpes virus (HHV)-8 gene expression patterns.
- Changes in human herpes virus (HHV)-8 viral load [ Time Frame: Baseline up to 12 months ]
Descriptive statistics such as frequencies and percentages will be used to aid in the evaluation of EBV and HHV-8 gene expression patterns.
- Changes in human immunodeficiency virus (HIV) viral load [ Time Frame: Baseline up to 12 months ]
A repeated measures analysis of variance will be used to assess the effect across time points.
- Event-free survival (EFS) (Phase II) [ Time Frame: 1 year ]
Binomial proportions and their 95% confidence intervals will be used to determine the 1-year EFS rate.
- Overall survival (OS) (Phase II) [ Time Frame: 1 year ]
Binomial proportions and their 95% confidence intervals will be used to determine the 1-year OS rates.
- Percentage of plasma associated human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) (Phase I) [ Time Frame: Baseline up to 12 months ]
Evaluated using analyses of variance. For each dose group and for all groups combined, the Wilcoxon signed rank test will be used to evaluate the changes in HIV viral load and CD4 count. If there is sufficient number of patients in each dose group, the Kruskal-Wallis test will be used to compare dose groups with respect to changes in HIV viral load and CD4 count.
- Pharmacokinetic profile and the parameters of clearance and the AUC (area under the curve) (Phase I) [ Time Frame: Up to 12 months ]
Summary statistics will be used to describe pharmacokinetic results by dose level. Comparisons across dose levels will be made to assess proportionality or variability of the different parameters.
- Tumor response rate (Phase I) [ Time Frame: Up to 5 years ]
The tumor response rate will be estimated for each dose group and for all groups combined. The 95% confidence intervals will be constructed for tumor response rates.
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- 1-year event-free survival
- 1-year overall survival
- Effect of treatment on HIV, HBV, and HHV-8 viral load
- Effect of treatment on T-cell subsets (CD4 and CD8) and plasma immunoglobulin levels
- Gene expression profiling
- EBV gene expression
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Not Provided
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Not Provided
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Vorinostat and Combination Chemotherapy With Rituximab in Treating Patients With HIV-Related Diffuse Large B-Cell Non-Hodgkin Lymphoma or Other Aggressive B-Cell Lymphomas |
A Sequential Phase I/Randomized Phase II Trial of Vorinostat and Risk-Adapted Chemotherapy With Rituximab in HIV-Related B-Cell Non-Hodgkin's Lymphoma |
This partially randomized phase I/II trial studies the side effects and the best dose of vorinostat when given together with combination chemotherapy and rituximab to see how well it works compared to combination chemotherapy alone in treating patients with human immunodeficiency virus-related diffuse large B-cell non-Hodgkin lymphoma or other aggressive B-cell lymphomas. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Giving vorinostat together with combination chemotherapy and rituximab may kill more cancer cells. |
PRIMARY OBJECTIVES:
I. Determine the recommended phase II dose (RPTD) of vorinostat that may be used in combination with dose-adjusted etoposide, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride and rituximab (R-DA-EPOCH) (in high-risk disease) in participants with human immunodeficiency virus (HIV)-associated aggressive cluster of differentiation (CD)20 positive non-Hodgkin lymphoma (NHL). (Phase I) II. Determine the overall toxicity rates of R-DA-EPOCH (in high-risk disease) with and without vorinostat. (Phase II) III. Determine the efficacy of the combinations of R-DA-EPOCH (in high-risk disease) with and without vorinostat in HIV-associated aggressive CD20 positive NHL using complete response (CR) rates as study endpoints. (Phase II)
SECONDARY OBJECTIVES:
I. Determine 1-year event-free survival (EFS) and 1 year overall survival (OS). II. Assess the effect of vorinostat and chemotherapy on latent HIV in memory T cells.
III. Assess the effect of vorinostat and/or chemotherapy on HIV, Epstein-Barr virus (EBV), and human herpes virus 8 (HHV-8) viral loads on banked specimens.
IV. Assess the effect of vorinostat and/or chemotherapy on T-cell subsets (CD4 and CD8) and plasma immunoglobulin levels.
V. Assess the effect of concurrent vorinostat and rituximab on plasma steady-state concentrations of etoposide, doxorubicin (doxorubicin hydrochloride), and vincristine (vincristine sulfate) (on Phase I only).
VI. Perform wide human gene expression profiling and methylation studies in tumors banked at baseline.
VII. Evaluate EBV and HHV-8 gene expression patterns in positive tumors banked at baseline.
OUTLINE: This is a phase I, dose-escalation study of vorinostat followed by a phase II study.
PHASE I: Patients receive vorinostat orally (PO) once daily (QD) on days 1-5; rituximab intravenously (IV) on day 1; etoposide IV over 24 hours, doxorubicin hydrochloride IV over 24 hours, and vincristine sulfate IV over 24 hours on days 1-4; prednisone PO daily on days 1-5; and cyclophosphamide IV over 1 hour on day 5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
PHASE II: Patients are randomized to 1 of 2 treatment arms.
ARM A (VR-DA-EPOCH): Patients receive vorinostat, rituximab, etoposide, doxorubicin hydrochloride, vincristine sulfate, prednisone, and cyclophosphamide as in Phase I.
ARM B (DA-R-EPOCH): Patients receive rituximab, etoposide, doxorubicin hydrochloride, vincristine sulfate, prednisone, and cyclophosphamide as in Arm A.
In all arms, treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for 3 years. |
Interventional |
Phase 1 Phase 2 |
Allocation: Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Treatment |
- AIDS-Related Plasmablastic Lymphoma
- AIDS-Related Primary Effusion Lymphoma
- CD20 Positive
- HIV Infection
- Plasmablastic Lymphoma
- Primary Effusion Lymphoma
- Recurrent Diffuse Large B-Cell Lymphoma
- Recurrent Grade 3 Follicular Lymphoma
- Stage I Diffuse Large B-Cell Lymphoma
- Stage I Grade 3 Follicular Lymphoma
- Stage II Diffuse Large B-Cell Lymphoma
- Stage II Grade 3 Contiguous Follicular Lymphoma
- Stage II Grade 3 Non-Contiguous Follicular Lymphoma
- Stage III Diffuse Large B-Cell Lymphoma
- Stage III Grade 3 Follicular Lymphoma
- Stage IV Diffuse Large B-Cell Lymphoma
- Stage IV Grade 3 Follicular Lymphoma
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- Drug: Cyclophosphamide
Given IV
Other Names:
- (-)-Cyclophosphamide
- 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
- Carloxan
- Ciclofosfamida
- Ciclofosfamide
- Cicloxal
- Clafen
- Claphene
- CP monohydrate
- CTX
- CYCLO-cell
- Cycloblastin
- Cycloblastine
- Cyclophospham
- Cyclophosphamid monohydrate
- Cyclophosphamidum
- Cyclophosphan
- Cyclophosphane
- Cyclophosphanum
- Cyclostin
- Cyclostine
- Cytophosphan
- Cytophosphane
- Cytoxan
- Fosfaseron
- Genoxal
- Genuxal
- Ledoxina
- Mitoxan
- Neosar
- Revimmune
- Syklofosfamid
- WR- 138719
- Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
- 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
- ADM
- Adriacin
- Adriamycin
- Adriamycin hydrochloride
- Adriamycin PFS
- Adriamycin RDF
- ADRIAMYCIN, HYDROCHLORIDE
- Adriamycine
- Adriblastina
- Adriblastine
- Adrimedac
- Chloridrato de Doxorrubicina
- DOX
- DOXO-CELL
- Doxolem
- Doxorubicin.HCl
- Doxorubin
- Farmiblastina
- FI 106
- FI-106
- hydroxydaunorubicin
- Rubex
- Drug: Etoposide
Given IV
Other Names:
- Demethyl Epipodophyllotoxin Ethylidine Glucoside
- EPEG
- Lastet
- Toposar
- Vepesid
- VP 16-213
- VP-16
- VP-16-213
- Other: Laboratory Biomarker Analysis
Correlative studies
- Other: Pharmacological Study
Correlative studies
- Drug: Prednisone
Given PO
Other Names:
- .delta.1-Cortisone
- 1, 2-Dehydrocortisone
- Adasone
- Cortancyl
- Dacortin
- DeCortin
- Decortisyl
- Decorton
- Delta 1-Cortisone
- Delta-Dome
- Deltacortene
- Deltacortisone
- Deltadehydrocortisone
- Deltasone
- Deltison
- Deltra
- Econosone
- Lisacort
- Meprosona-F
- Metacortandracin
- Meticorten
- Ofisolona
- Orasone
- Panafcort
- Panasol-S
- Paracort
- PRED
- Predicor
- Predicorten
- Prednicen-M
- Prednicort
- Prednidib
- Prednilonga
- Predniment
- Prednisonum
- Prednitone
- Promifen
- Servisone
- SK-Prednisone
- Biological: Rituximab
Given IV
Other Names:
- ABP 798
- BI 695500
- C2B8 Monoclonal Antibody
- Chimeric Anti-CD20 Antibody
- CT-P10
- IDEC-102
- IDEC-C2B8
- IDEC-C2B8 Monoclonal Antibody
- MabThera
- Monoclonal Antibody IDEC-C2B8
- PF-05280586
- Rituxan
- Rituximab Biosimilar ABP 798
- Rituximab Biosimilar BI 695500
- Rituximab Biosimilar CT-P10
- Rituximab Biosimilar IBI301
- Rituximab Biosimilar PF-05280586
- Rituximab Biosimilar RTXM83
- Rituximab Biosimilar SAIT101
- RTXM83
- Drug: Vincristine Sulfate
Given IV
Other Names:
- Kyocristine
- Leurocristine Sulfate
- Leurocristine, sulfate
- Oncovin
- Vincasar
- Vincosid
- Vincrex
- Vincristine, sulfate
- Drug: Vorinostat
Given PO
Other Names:
- L-001079038
- MSK-390
- SAHA
- Suberanilohydroxamic Acid
- Suberoylanilide Hydroxamic Acid
- Zolinza
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- Experimental: Arm A (VR-DA-EPOCH)
Patients receive vorinostat PO QD on days 1-5; rituximab IV on day 1; etoposide IV over 24 hours, doxorubicin hydrochloride IV over 24 hours, and vincristine sulfate IV over 24 hours on days 1-4; prednisone PO daily on days 1-5; and cyclophosphamide IV over 1 hour on day 5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Interventions:
- Drug: Cyclophosphamide
- Drug: Doxorubicin Hydrochloride
- Drug: Etoposide
- Other: Laboratory Biomarker Analysis
- Other: Pharmacological Study
- Drug: Prednisone
- Biological: Rituximab
- Drug: Vincristine Sulfate
- Drug: Vorinostat
- Experimental: ARM B (DA-R-EPOCH)
Patients receive rituximab, etoposide, doxorubicin hydrochloride, vincristine sulfate, prednisone, and cyclophosphamide as in Arm A. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Interventions:
- Drug: Cyclophosphamide
- Drug: Doxorubicin Hydrochloride
- Drug: Etoposide
- Other: Laboratory Biomarker Analysis
- Other: Pharmacological Study
- Drug: Prednisone
- Biological: Rituximab
- Drug: Vincristine Sulfate
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Not Provided |
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Active, not recruiting |
112 |
130 |
Not Provided |
October 14, 2016 (Final data collection date for primary outcome measure) |
Inclusion Criteria:
Exclusion Criteria:
- Participants who have received more than one (1) prior cycle of chemotherapy similar to cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP) or EPOCH with or without rituximab
- Absolute CD4 count of < 50 cells/ mm^3
- Presence of second active tumor, other than non-melanoma skin cancer, carcinoma in situ of the cervix, or Kaposi's sarcoma (KS) that requires systemic therapy
- Central nervous system (CNS) involvement by lymphoma including parenchymal brain or spinal cord lymphoma or known presence of leptomeningeal disease prior to registration
- Participants with viral hepatitis who do not meet the criteria will not be eligible; all participants who present with acute hepatitis B including those with normal transaminases who are HBsAg+ and IgM + for hepatitis core antigen will not be eligible; participants who are hepatitis B core antibody positive are eligible only if they start or are on prophylactic therapy; a hepatitis B viral load should be confirmed negative on all participants who are hepatitis B core antibody positive, but hepatitis B antigen negative; participants refusing to take any anti-hepatitis B therapy during study will also be excluded; participants diagnosed with hepatitis C are eligible if they meet criteria
- Pregnant women or nursing mothers
- ECOG performance score >= 3 (Karnofsky performance status [KPS] < 50%)
- Expected survival < 2 months
- Unable to comply with the requirements of the protocol, or unable to provide adequate informed consent in the opinion of the principal investigator
- Serious, ongoing, non-malignant disease or infection, which in the opinion of the investigator and/or the sponsor would compromise other protocol objectives; participants with active opportunistic infections are ineligible
- Major surgery, other than diagnostic surgery, occurring 4 weeks prior to study entry; splenectomy will not be considered an exclusionary major surgery
- Rituximab therapy within the 12 months prior to study entry; participants treated with rituximab within 12 months prior to study registration are eligible only if it was given for indications other than the treatment of aggressive lymphoma
- Prior cytotoxic chemotherapy or radiotherapy for this lymphoma
- History of cutaneous or mucocutaneous reactions, or diseases in the past, due to any cause, severe enough to cause hospitalization or an inability to eat or drink for > 2 days; this exclusion relates to the long-term possibility of severe cutaneous or mucocutaneous reactions to rituximab that might occur at increased frequency in participants who have had severe skin disease or reactions in the past
- Use of zidovudine or cobicistat as part of the HAART regimen (a drug substitution at the time of study entry is allowed)
- Any acute, inter-current infection that may interfere with planned protocol treatment; participants with mycobacterium avium will not be excluded from study entry; chronic therapy with potentially myelosuppressive agents is allowed provided that entry hematologic criteria are met
- Myocardial infarction (MI) within 6 months prior to study entry, New York Heart Association (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities
- Participants should not have taken valproic acid or another histone deacetylase inhibitor for at least 2 weeks prior to study enrollment
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Sexes Eligible for Study: |
All |
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18 Years and older (Adult, Senior) |
No |
Contact information is only displayed when the study is recruiting subjects |
United States |
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NCT01193842 |
NCI-2011-02508 NCI-2011-02508 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) AMC #75 CDR0000683379 AMC-075 ( Other Identifier: AIDS Malignancy Consortium ) AMC-075 ( Other Identifier: DCP ) AMC-075 ( Other Identifier: CTEP ) UM1CA121947 ( U.S. NIH Grant/Contract ) |
No |
Not Provided |
Not Provided |
National Cancer Institute (NCI) |
National Cancer Institute (NCI) |
Not Provided |
Principal Investigator: |
Juan Ramos |
AIDS Malignancy Consortium |
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National Cancer Institute (NCI) |
May 2017 |