Vorinostat Plus FND in Relapsed or Refractory Mantle Cell Lymphoma (ZOLINZA)

Samsung Medical Center

Status and phase: Terminated; Phase 2

Conditions: Mantle Cell Lymphoma

Treatments: Drug: Fludarabine, Mitoxantrone, Dexamethasone, Vorinostat

Study type: Interventional

Funder types: Other

Identifiers

NCT01578343

SMC2011-11-102-001

Details and patient eligibility

About

1. Rationale In mantle cell lymphoma, the conventional chemotherapy achieves only temporary responses with a median duration of remissions only from 1 to 2 years. Therefore, mantle cell lymphoma is known as one of the B-cell lymphomas with poor prognosis. Although the treatment outcome of mantle cell lymphoma has been improved since intensive chemotherapy regimens such as HyperCVAD was used, a substantial number of patients are still frequently relapsed after chemotherapy. After relapse, most of them became refractory to various kinds of salvage treatment. That is why the results of most salvage chemotherapy regimens were disappointing. In addition, mantle cell lymphoma generally occurs in elderly people. Thus, intensive salvage chemotherapy may not be feasible for elderly patients. Therefore, an effective, novel combination treatment is urgently needed in relapsed or refractory mantle cell lymphoma patients.

2. Hypothesis

   • Vorinostat will produce synergism with a combination treatment regimen (Fludarabine, mitoxantrone, dexamethasone, FND) without overlapping toxicity
   • Vorinostat maintenance treatment will reduce the relapse rate in patients ineligible for autologous stem cell transplantation.

3. Purpose A phase II investigation to determin the effectiveness of vorinostat in combination with intravenous fludarabine, mitoxantrone, and dexamethasone in patients with relapsed or refractory mantle cell lymphomain patients with relapsed or refractory mantle cell lymphoma.

Full description

1. Objectives 1.1 Primary objective • To determine the efficacy of vorinostat plus FND as an induction treatment

   • Response rate of vorinostat/FND 1.2 Secondary objective

     • Survival outcome

   • Overall survival and progression-free survival

     • To determine the efficacy of vorinostat maintenance treatment

   • Relapse rate • Toxicity of vorinostat/FND

   • Hematologic and non-hematologic toxicity

Enrollment: 20 patients

Sex: All

Ages: 19 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

1. Inclusion

   • Histologically proven mantle cell lymphoma

   • Adequate organ function as defined by the following criteria:

     • Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase (SGOT)) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase (SGPT)) ≤2.5 x local laboratory upper limit of normal (ULN), or AST and ALT less than or equal to 5 x ULN if liver function abnormalities are due to underlying malignancy
     • Total serum bilirubin ≤1.5 x ULN
     • Absolute neutrophil count (ANC) ≥1500/µL
     • Platelets ≥100,000/µL
     • Hemoglobin ≥9.0 g/dL (may be transfused or erythropoietin treated)
     • Serum calcium ≤12.0 mg/dL
     • Serum creatinine ≤1.5 x ULN
     • Normal potassium and magnesium at baseline

   • All patients should be relapsed or refractory patients after previous treatments including chemotherapy .

   • At least one measurable lesion (lymph node or tumor mass)

     • The size of lesion must be > 1.0cm in the greatest transverse diameter

   • ECOG PS 0-2

   • Serum HCG test: negative if a patient is female eligible for pregnancy

2. Exclusion

   • Major surgery or radiation therapy within 4 weeks of starting the study treatment.
   • History of or known carcinomatous meningitis, or evidence of symptomatic leptomeningeal disease or secondary CNS involvement on CT or MRI scan.
   • Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2.
   • Pregnancy or breastfeeding.
   • Patients with HIV positive
   • Patients with HBs antigen positive
   • Patients with anti-HCV positive
   • History of the use of another HDAC inhibitor: e.g. valproic acid

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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20 participants in 1 patient group

Vorinostat-FND

Experimental group

Description:

Vorinostat-fludarabine, mitoxantrone, dexamethasone Induction treatment (Total 4 cycles) FND D1-3 Fludarabine 25mg/m2 + NS 100mL iv over 30 min D1 Mitoxantrone 10mg/m2 + NS 100mL iv over 30 min D1-5 Dexamethasone 20mg IV or PO every 4 weeks Vorinostat D1-10 Vorinostat 200mg once daily PO (When vorinostat is concurrently administered with FND regimen, vorinostat will be administered 3 hours before chemotherapy)

Treatment:

Drug: Fludarabine, Mitoxantrone, Dexamethasone, Vorinostat