Clinical trial NCT01193842: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: AIDS-Related Plasmablastic Lymphoma
AIDS-Related Primary Effusion Lymphoma
Ann Arbor Stage I Diffuse Large B-Cell Lymphoma
Ann Arbor Stage I Grade 3 Follicular Lymphoma
Ann Arbor Stage II Diffuse Large B-Cell Lymphoma
Ann Arbor Stage II Grade 3 Contiguous Follicular Lymphoma
Ann Arbor Stage II Grade 3 Non-Contiguous Follicular Lymphoma
Ann Arbor Stage III Diffuse Large B-Cell Lymphoma
Ann Arbor Stage III Grade 3 Follicular Lymphoma
Ann Arbor Stage IV Diffuse Large B-Cell Lymphoma
Ann Arbor Stage IV Grade 3 Follicular Lymphoma
HIV Infection
Plasmablastic Lymphoma
Primary Effusion Lymphoma
Recurrent Diffuse Large B-Cell Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-09-02
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Participants with histologically or cytologically documented diffuse large B-cell lymphoma (DLBCL) must meet at least 1 of the following risk criteria:

  * Age-adjusted International Prognostic Index (IPI) score: 2-3
  * Ki-67 \>= 80%
  * Histologically, or cytologically documented activated B-cell-like (ABC, also known as post-GCB) subtype
  * Double hit variant, defined as having v-myc avian myelocytomatosis viral oncogene homolog (MYC) gene rearrangement in the presence of B-cell chronic lymphocytic leukemia (CLL)/lymphoma (BCL) 2 or BCL6 gene rearrangement

    * Other aggressive non-DLBCL non-Burkitt non-Hodgkin B-cell lymphoma variants as defined by the 2008 World Health Organization (WHO) classification, including rare CD20 negative B-cell lymphomas (i.e. plasmablastic lymphoma, and primary effusion lymphoma) are also eligible; grade 3B follicular lymphoma is also eligible as long as one the above risk criteria is met
* Participants who are untreated or who received a maximum of one (1) cycle of combination chemotherapy, including rituximab-containing regimens, prior are eligible; the start of previous chemotherapy cycle must occur at least 21 days prior to beginning treatment under this protocol, and such cycle will count towards the total maximum of 6 cycles under this study
* Documentation of HIV infection at any time prior to study entry; documentation may be molecular (detectable viral ribonucleic acid \[RNA\] by polymerase chain reaction \[PCR\]), serologic (positive enzyme-linked immunosorbent assay \[ELISA\] and positive Western blot), or other federally approved licensed HIV test; prior documentation of HIV seropositivity is acceptable
* All stages of disease
* Measurable or non-measurable tumor parameter(s); non-measurable tumor parameters are defined as not having bidimensional measurements (e.g., gastric or marrow involvement), but can be followed for response by other diagnostic tests such as gallium, positron emission tomography (PET) imaging, and/or bone marrow biopsy
* Performance status (PS) 0, 1, or 2 per the Eastern Cooperative Oncology Group (ECOG) performance status scale (Karnofsky performance score \>= 50%)
* Able to provide informed consent
* Total bilirubin =\< 1.5 institutional upper limit of normal (ULN), unless elevated secondary to lymphomatous involvement of liver or biliary system, or due to other HIV medications (e.g., indinavir, tenofovir, or atazanavir); for direct bilirubin \> 1.2 due to hepatic involvement by tumor for the initial dose of EPOCH drug adjustment
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 times ULN (unless elevated due to secondary lymphomatous involvement of the liver)
* Negative for hepatitis B, or if infected with hepatitis B, receiving anti-hepatitis B therapy; all participants will be required to be screened for hepatitis B and C; per Infectious Disease Society of America (IDSA) and American Association for the Study of Liver Diseases (AASD) guidelines, those participants that show no immunity, defined by the lack of hepatitis B surface antibody, and show evidence of chronic infection (i.e. hepatitis B surface antigen positive \[HBsAg+\], hepatitis B core antibody positive \[HBcore+\], hepatitis surface antibody negative \[HBsAB-\]) will be required to be on anti-hepatitis B therapy, during the study, in order to be eligible; participants will be permitted to enroll in the study provided liver function tests meet criteria, and there is no evidence of cirrhosis; the exact hepatitis B therapy will be at the discretion of the infection disease specialist or investigator; however all participants who present with acute hepatitis B or show normal transaminases and are HBsAg+ and immunoglobulin (Ig)M+ for hepatitis core antigen will not be eligible for trial enrollment; participants who are hepatitis C antibody positive, with or without a positive hepatitis C RNA level, will be permitted to enroll in the study provided liver function tests meet criteria, and have no evidence of cirrhosis; participants diagnosed with hepatitis C less than 6 months from trial enrollment, will be considered to have acute hepatitis C and will be excluded from study unless hepatitis (hep) C viral load is undetectable
* Creatinine clearance \>= 60 mL/min, unless secondary to renal involvement by lymphoma; for creatinine clearance \< 50 mL/min due to kidney involvement by tumor
* Granulocytes/absolute neutrophil count (ANC) \>= 1,000/mm\^3
* Platelets \>= 75,000/mm\^3 (unless these parameters are abnormal secondary to lymphomatous involvement of bone marrow); all participants must cease colony-stimulating factor therapy at least 24 hours prior to institution of cycle 1 chemotherapy
* Left ventricular ejection fraction (LVEF) that is at or above the lower institutional limits of normal, as assessed by multiple gated acquisition (MUGA) scan or echocardiogram within the 6 weeks prior to registration
* Concurrent radiation, with or without steroids, or steroids alone for emergency conditions secondary to lymphoma (i.e. cord compression, etc.) will be permitted
* Female participants must have a negative pregnancy test within 7 days of entering into the study; both men and women of child bearing potential must agree to use adequate methods of contraception for the duration of the treatment; women must avoid pregnancy, and men must avoid fathering children while in the study and for 6 months following the last study drug treatment
* Participants on an antiretroviral regimen should be receiving treatment that is in accordance with the current International acquired immune deficiency syndrome (AIDS) Society guidelines; the specific agents are at the discretion of the investigator and use of agents currently available on an expanded access basis is allowed but use of experimental antiretroviral agents or those containing zidovudine (including Combivir and Trizivir) are prohibited; changes to highly active anti-retroviral therapy (HAART) therapy may be made if medically necessary (toxicity, failure of regimen, etc.); antiretroviral naïve participants: participants who are not on HAART at study entry MUST begin therapy (utilizing the above guidelines) AFTER one cycle of chemotherapy has been completed under protocol; changes to HAART therapy may be made if medically necessary (toxicity, failure of regimen, etc.); concurrent therapy with zidovudine or a zidovudine-containing regimen (including Combivir and Trizivir) will be prohibited until 2 months following the participant's completion of chemotherapy as part of this protocol; the use of cobicistat (e.g., Tybost), or cobicistat containing single tablet regimens (e.g., Stribild) is prohibited during concurrent chemotherapy under this protocol; participants taking cobicistat or cobicistat-containing single table regimens must switch to a different agent or regimen prior to enrollment, and will remain on the regimen until at least 2 months following treatment discontinuation; Cobicistat is a pure and potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitor and has the potential to increase the area under the curve (AUC) of CYP3A4 substrates; therefore, both vincristine and doxorubicin would have the potential for drug drug interaction (DDI) with cobicistat since they are CYP3A4 substrates
* Participants already receiving erythropoietin or colony-stimulating factor therapy are eligible for participation, although the latter must be discontinued at least 24 hours prior to receiving chemotherapy
* Participants must be able to swallow oral medications

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

Primary outcomes:
measure: Percentage of Participants With Complete Response (CR) as Assessed by Response Evaluation Criteria in Solid Tumors (Phase II)
timeFrame: Up to 6 months
measure: Percentage of Participant Experiencing Adverse Events (AEs) for Each Treatment Arm as Assessed by Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0) (Phase II)
timeFrame: Up to 5 years
measure: 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)
timeFrame: 21 days
Secondary outcomes:
measure: Change in CD8 Cell Counts (Phase I)
timeFrame: Baseline up to 12 months
measure: Changes in Absolute CD4 Cell Counts (Phase I)
timeFrame: Baseline up to 12 months
measure: Changes in Epstein-Barr Virus (EBV) Viral Load
timeFrame: Baseline up to 12 months
measure: Changes in Human Herpes Virus (HHV)-8 Viral Load
timeFrame: Baseline up to 12 months
measure: Changes in Human Immunodeficiency Virus (HIV) Viral Load
timeFrame: Baseline up to 12 months
measure: Event-free Survival (EFS) (Phase II)
timeFrame: 1 year
measure: Overall Survival (OS) (Phase II)
timeFrame: 1 year
measure: Change in Plasma Associated Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (Phase I)
timeFrame: Baseline up to 12 months
measure: Pharmacokinetic Clearance (Phase I)
timeFrame: 24-48, 48-72, and 72-96 hours after the start of the first chemotherapy infusion
measure: Tumor Response (Phase I)
timeFrame: Up to 2 years post treatment
Other outcomes:
Locations:
city: Montgomery
country: United States
facility: Jackson Hospital and Clinic
state: Alabama
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Center for Clinical AIDS Research and Education
state: California
city: Los Angeles
country: United States
facility: UCLA / Jonsson Comprehensive Cancer Center
state: California
city: San Diego
country: United States
facility: San Diego VA Medical Center
state: California
city: San Francisco
country: United States
facility: Zuckerberg San Francisco General Hospital
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Parnassus
state: California
city: Miami
country: United States
facility: Jackson Memorial Hospital-Holtz Children's Hospital
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Miami
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Kendall
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: John H Stroger Jr Hospital of Cook County
state: Illinois
city: Chicago
country: United States
facility: Stroger Hospital of Cook County MBCCOP
state: Illinois
city: New Orleans
country: United States
facility: Louisiana State University Health Science Center
state: Louisiana
city: New Orleans
country: United States
facility: University Medical Center New Orleans
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Washington University
state: Missouri
city: Saint Louis
country: United States
facility: Washington University - Jewish
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center-Einstein Campus
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center-Weiler Hospital
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Pennsylvania Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Miriam Hospital
state: Rhode Island
city: Houston
country: United States
facility: Thomas Street Clinic
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
state: Texas
city: Houston
country: United States
facility: Ben Taub General Hospital
state: Texas
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
Study officials:
affiliation: AIDS Malignancy Consortium
name: Juan C Ramos
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ramos JC, Sparano JA, Chadburn A, Reid EG, Ambinder RF, Siegel ER, Moore PC, Rubinstein PG, Durand CM, Cesarman E, Aboulafia D, Baiocchi R, Ratner L, Kaplan L, Capoferri AA, Lee JY, Mitsuyasu R, Noy A. Impact of Myc in HIV-associated non-Hodgkin lymphomas treated with EPOCH and outcomes with vorinostat (AMC-075 trial). Blood. 2020 Sep 10;136(11):1284-1297. doi: 10.1182/blood.2019003959.