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

Brief Title

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

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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Percentage of Participants With Complete Response (CR) as Assessed by Response Evaluation Criteria in Solid Tumors (Phase II)

Secondary Outcome

 Change in CD8 Cell Counts (Phase I)

Condition

AIDS-Related Plasmablastic Lymphoma

Intervention

Cyclophosphamide

Study Arms / Comparison Groups

 Arm A (VR-DA-EPOCH)
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

107

Start Date

October 6, 2010


Primary Completion Date

November 12, 2016

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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Juan C Ramos, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01193842

Organization ID

NCI-2011-02508

Secondary IDs

NCI-2011-02508

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Juan C Ramos, Principal Investigator, AIDS Malignancy Consortium


Verification Date

June 2021