Study of Bortezomib and Panobinostat in Treating Patients With Relapsed/Refractory Peripheral T-cell Lymphoma or NK/T-cell Lymphoma

NCT ID: NCT00901147

Last Updated: 2014-06-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-11-30
• Study Completion Date: 2014-01-31

Brief Summary

The purpose of this study is to determine whether intravenous Bortezomib combined with oral Panobinostat (LBH589) are effective in treating adult patients with relapsed/refractory peripheral T-cell lymphoma or NK/T-cell lymphoma after the failure of conventional chemotherapy.

Detailed Description

Peripheral T-cell lymphoma (PTCL) and NK/T-cell lymphoma are uncommon diseases that are prevalent in Asia. They are associated with poor prognosis when treated with conventional chemotherapeutic regimes. Their long term disease-free survivals are dismal with only 10-30% of patients surviving long term. More intensive regimens including high dose chemotherapy with autologous stem cell transplant have been tried as primary induction treatment, but have not been shown to be beneficial. Given the rarity of PTCL and NK/T-cell lymphoma, much of the literature consists of studies with small sample size and anecdotal case reports. Therefore, no consensus exists on the best therapeutic strategy for either newly diagnosed or relapsed disease. The failure of conventional chemotherapy in this regard suggests that novel therapies including epigenetic approaches and proteasome inhibition should be explored.

Preclinical data of bortezomib and histone deacetylase inhibitors (HDIs) in T-cell and NK/T-cell lymphoma cell lines are encouraging. Bortezomib and HDIs have also separately demonstrated activity in T and NK/T-cell lymphomas in phase II studies, leading to their separate developments in phase III studies. Demonstration of synergism in these 2 agents, in part due to their dependence on overlapping pathways, suggests that they should be explored as a combination, especially when treating a disease with a very unfavourable outcome. The purpose of this phase II study is to assess the efficacy of orally-administered panobinostat, a potent class I/II pan-deacetylase inhibitor with intravenous bortezomib in this patient population.

Conditions

Peripheral T-cell Lymphoma (Not Otherwise Specified); Angioimmunoblastic T-cell Lymphoma; Extranodal NK/T-cell Lymphoma Nasal Type; Enteropathy- Type T-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Anaplastic Large Cell Lymphoma (ALCL) (ALK-1 Negative); Relapsed ALCL (ALK-1 Positive) Post Autologous Transplant

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

panobinostat and bortezomib

Oral Panobinostat and intravenous bortezomib

Group Type: EXPERIMENTAL

panobinostat and bortezomib

Intervention Type: DRUG

oral panobinostat 30 mg 3 times per week AND intravenous bortezomib 1.3mg/m2 on days 1,4,8,11 per cycle

Interventions

panobinostat and bortezomib

oral panobinostat 30 mg 3 times per week AND intravenous bortezomib 1.3mg/m2 on days 1,4,8,11 per cycle

Intervention Type: DRUG

Other Intervention Names

LBH589B; Velcade

Eligibility Criteria

Inclusion Criteria

• Histologically confirmed PTCL NOS, angioimmunoblastic T-cell lymphoma, extranodal NK/T-cell lymphoma nasal type, enteropathy- type T-cell lymphoma, hepatosplenic T-cell lymphoma, ALCL (ALK-1 negative), or patients with ALK 1 expressing ALCL (ALK-1 positive) who have relapsed disease after ASCT
• Age ≥21 years
• Written informed consent
• Progressive disease following at least one systemic therapy or refractory to at least one prior systemic therapy
• Measurable disease according to the IWC criteria and/or measurable bone marrow disease by flow cytometry or morphology
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Absolute neutrophil count of ≥1000 × 10(9)cells/L
• Negative urine or serum pregnancy test on females of childbearing potential
• All females of childbearing potential and males must use an effective barrier method of contraception during the treatment period and for at least 1 month thereafter.

• Concomitant use of drugs that may cause a prolongation of the QTcF
• Concomitant use of CYP3A4 inhibitors
• Impaired liver, renal or other organ function not caused by lymphoma, which will interfere with the treatment schedule
• Concomitant use of warfarin due to a potential drug interaction
• Clinically significant active infection
• Known infection with human immunodeficiency virus (HIV)
• Patient has known clinically active hepatitis B or C
• Previous extensive radiotherapy involving ≥30% of bone marrow (e.g., whole pelvis, half spine), excluding patients who have had total body irradiation as part of a conditioning regimen for stem cell transplant
• Major surgery within 2 weeks of study entry
• Peripheral neuropathy or neuropathic pain of Grade 2 or worse
• Platelet count <50 × 109 cells/L or platelet count <30 × 109 cells/L if bone marrow disease involvement is documented
• Serum creatinine >2.0 × ULN
• Patients who are pregnant or breast-feeding
• Patient has known hypersensitivity to any components of bortezomib (such as boron, mannitol), or panobinostat

Exclusion Criteria

• Chemotherapy or immunotherapy within 3 weeks of study entry
• Concomitant use of any other anti-cancer therapy
• Concomitant use of any other investigational agent
• Any known cardiac abnormalities such as:

• Congenital long QT syndrome;
• QTcF interval >480 milliseconds (msec);
• A myocardial infarction within 12 months of study entry;
• Other significant ECG abnormalities including 2nd atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate < 50 beats/ min).
• An ECG recorded at screening showing significant ST depression (ST depression of ≥2 mm, measured from isoelectric line to the ST segment at a point 60 msec at the end of the QRS complex). If in any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
• Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction <40% by MUGA scan or <50% by echocardiogram and/or MRI;
• A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD);
• Hypertrophic cardiomyopathy or restrictive cardiomyopathy from prior treatment or other causes (if in doubt, see ejection fraction criteria above);
• Any cardiac arrhythmia requiring anti-arrhythmic medication;

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Singapore General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Yeow Tee Goh, MBBS MMed

Role: PRINCIPAL_INVESTIGATOR

Singapore General Hospital

Darryl Tan, MBBS MMED

Role: STUDY_CHAIR

Singapore General Hospital

Locations

Hospital Universiti Kebangsaan Malaysia ( HUKM )

Kuala Lumpur, Kuala Lumpur, Malaysia

Subang Jaya Medical Centre

Subang Jaya, Selangor, Malaysia

National Cancer Center

Singapore, , Singapore

Singapore General Hospital

Singapore, , Singapore

Samsung Medical Centre

Seoul, Seoul, South Korea

Countries

Malaysia; Singapore; South Korea

References

Tan D, Phipps C, Hwang WY, Tan SY, Yeap CH, Chan YH, Tay K, Lim ST, Lee YS, Kumar SG, Ng SC, Fadilah S, Kim WS, Goh YT; SGH651 Investigators. Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: an open-label, multicentre phase 2 trial. Lancet Haematol. 2015 Aug;2(8):e326-33. doi: 10.1016/S2352-3026(15)00097-6. Epub 2015 Jul 7.

Reference Type: DERIVED

PMID: 26688485 (View on PubMed)

Other Identifiers

SHF/CTG023/2008

Identifier Type: -

Identifier Source: secondary_id

SGH651

Identifier Type: -

Identifier Source: org_study_id