Clinical trial NCT00561418: Vorinostat After Stem Cell Transplant in Treating Patients With High-Risk Lymphoma
Official title: Histone Deacetylase (HDAC) Inhibition Using Vorinostat (SAHA) After Autologous Hematopoietic Stem Cell Transplantation for High Risk Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphoma
Small Intestine Cancer
Keywords: recurrent adult diffuse large cell lymphoma
stage III adult diffuse large cell lymphoma
stage IV adult diffuse large cell lymphoma
recurrent grade 3 follicular lymphoma
recurrent adult Hodgkin lymphoma
recurrent mantle cell lymphoma
adult nasal type extranodal NK/T-cell lymphoma
angioimmunoblastic T-cell lymphoma
recurrent adult T-cell leukemia/lymphoma
stage III adult T-cell leukemia/lymphoma
stage IV adult T-cell leukemia/lymphoma
small intestine lymphoma
anaplastic large cell lymphoma
Lead sponsor: Ohio State University Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2007-11-21
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth, and may stimulate the immune system to stop cancer cells from growing.

PURPOSE: This phase I trial is studying the side effects and best dose of vorinostat after stem cell transplant in treating patients with high-risk lymphoma.

Detailed description: OBJECTIVES:

Primary

* To assess dose-limiting and nonhematologic toxicity of prolonged administration of vorinostat (SAHA) when administered after autologous peripheral blood stem cell transplantation in patients with high-risk lymphoma.

Secondary

* To determine, preliminarily, clinical activity by assessing the overall survival and progression-free survival.
* To evaluate the effect of vorinostat on immune reconstruction and acetylation.
* To obtain pilot data regarding an association of vorinostat with patient quality of life and inflammatory cytokine production of peripheral blood mononuclear cells.

OUTLINE: This is a dose-escalation study of vorinostat (SAHA).

Approximately 60 days after autologous hematopoietic stem cell transplantation (HSCT), patients receive oral vorinostat once daily on days 1-21. Treatment repeats every 28 days for up to 11 courses in the absence of unacceptable toxicity or disease progression.

Blood and bone marrow samples are collected periodically for laboratory correlative studies comprising immune reconstitution assays, regulatory T-cell expansion analysis, H3 and H4 acetylation by immunohistochemistry, cytokine bead array to quantify interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, tumor necrosis factor alpha and interferon gamma. Quality of life correlative studies are measured by questionnaires periodically.

After completion of study treatment, patients are followed for at least 30 days.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Must have received a BEAM (cytarabine, etoposide, melphalan, carmustine)-conditioned autologous stem cell transplantation for any of the following high-risk lymphomas:

  * Diffuse large B-cell lymphoma as defined by:

    * Induction failure but with response to salvage therapy
    * Relapse less than one year after completion of induction therapy
    * Elevated lactate dehydrogenase (LDH) at relapse
    * Stage III/IV disease at relapse
    * Positive PET scan after induction or salvage therapy
    * Age ≤ 75 and ≥ 60 years
  * Follicular lymphoma as defined by:

    * Progressive disease after two or more prior regimens
    * Transformed to aggressive lymphoma but still chemotherapy sensitive
    * Not felt to be a good candidate for an allogeneic transplantation
  * Hodgkin lymphoma as defined by:

    * Primary refractory disease
    * Relapse less than one year after completion of induction therapy
    * Relapse with PET-positive disease after salvage therapy
    * Relapsed refractory and not felt to be a good candidate for an allogeneic transplantation
  * Mantle cell lymphoma

    * Chemotherapy-sensitive disease after induction therapy
    * Chemotherapy-sensitive relapsed disease and not felt to be a good candidate for an allogeneic transplantation
  * T-cell non-Hodgkin lymphoma (NHL)

    * Peripheral T-cell lymphoma not otherwise specified and one or more of the following at diagnosis:

      * High LDH
      * Marrow involvement
      * Age \> 60 years
      * Low platelet count
      * Relapsed chemotherapy-sensitive disease
    * Angioimmunoblastic lymphadenopathy with dysproteinemia
    * Anaplastic lymphoma kinase-negative anaplastic NHL
    * Enteropathy-associated T-cell NHL
    * Natural killer (NK)/T-cell NHL and stage III/IV disease at diagnosis
    * NK blastic NHL

PATIENT CHARACTERISTICS:

* ECOG (Eastern Cooperative Oncology Group) /WHO performance status 0-2
* ANC (absolute neutrophil count) ≥ 1,000/μL
* Platelet count ≥ 75,000/μL
* Total bilirubin ≤ 1.5 mg/dL
* AST (aspartate aminotransferase)/ALT (Alanine transaminase) ≤ 2 x upper limit of normal (ULN)
* Serum creatinine ≤ 1.5 x ULN OR creatinine clearance ≥ 50 mL/min
* No severe or uncontrolled systemic illness
* Patients must be able to swallow capsules
* Negative pregnancy test
* Not pregnant or nursing
* Fertile patients must use at least two adequate barrier methods of contraception during study and for 90 days after completion of study therapy
* No other malignancy within the past 5 years other than nonmelanoma skin cancer, carcinoma in situ of the cervix, or a malignancy considered by their physician to be at less than 30% risk of relapse
* No congenital long QT syndrome
* No significant history of uncontrolled cardiac disease (i.e., uncontrolled hypertension, unstable angina, myocardial infarction within the past 6 months, or uncontrolled congestive heart failure)
* No active bacterial, fungal, or viral infection
* No known HIV infection
* No active hepatitis B and/or hepatitis C infection
* No other medical condition, including mental illness or substance abuse, deemed by the Investigator(s) to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results

PRIOR CONCURRENT THERAPY:

* Recovered from the majority of the toxicities from the autologous transplantation (must have returned to their pretransplant baseline or have no greater than grade I extramedullary toxicity Common Toxicity Criteria for Adverse Effects\[CTCAE 3.0\])
* No prior treatment with a histone deacetylase (HDAC) inhibitor (e.g., depsipeptide, MS-275, LAQ-824, belinostat, valproic acid)
* More than 4 weeks since prior and no concurrent class Ia, Ib, or Ic antiarrhythmic drugs
* No other concurrent antineoplastic chemotherapy or biologic therapy
* No concurrent radiotherapy, unless for local control of bone pain

  * Irradiated area for pain management should be as small as possible and lesions within the irradiated field cannot be used for response
* No concurrent use of complementary or alternative medicines that would confound the interpretation of toxicities and antitumor activity of vorinostat (SAHA)

Primary outcomes:
measure: Safety and Tolerability of Vorinostat (SAHA) After Autologous Stem Cell Transplantation
timeFrame: Up to 3 years
Secondary outcomes:
measure: Clinical Benefit
timeFrame: Up to 3 years
measure: Duration of Response
timeFrame: Up to 5 years
measure: Time to Progression
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
Study officials:
affiliation: Ohio State University Comprehensive Cancer Center
name: Craig C. Hofmeister, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hofmeister CC, Williams N, Geyer S, Hade EM, Bowers MA, Earl CT, Vaughn J, Bingman A, Humphries K, Lozanski G, Baiocchi RA, Jaglowski SM, Blum K, Porcu P, Flynn J, Penza S, Benson DM, Andritsos LA, Devine SM. A phase 1 study of vorinostat maintenance after autologous transplant in high-risk lymphoma. Leuk Lymphoma. 2015 Apr;56(4):1043-9. doi: 10.3109/10428194.2014.963073. Epub 2014 Nov 20.