Study of Bortezomib and Panobinostat in Treating Patients With Relapsed/Refractory Peripheral T-cell Lymphoma or NK/T-cell Lymphoma
Primary Purpose
Peripheral T-cell Lymphoma (Not Otherwise Specified), Angioimmunoblastic T-cell Lymphoma, Extranodal NK/T-cell Lymphoma Nasal Type
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
panobinostat and bortezomib
Sponsored by
About this trial
This is an interventional treatment trial for Peripheral T-cell Lymphoma (Not Otherwise Specified) focused on measuring t-cell lymphoma, peripheral t-cell lymphoma, nk/t-cell lymphoma, nasal type, bortezomib, velcade, panobinostat, LBH589b, histone deacetylase inhibitor, proteasome inhibitor
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
- Serum potassium ≥3.8 mmol/L and magnesium ≥0.85 mmol/L (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria)
- 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.
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;
- Serum potassium <3.8 mmol/L or serum magnesium <0.85 mmol/L (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria)
- 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
Sites / Locations
- Samsung Medical Centre
- Subang Jaya Medical Centre
- Hospital Universiti Kebangsaan Malaysia ( HUKM )
- National Cancer Center
- Singapore General Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
panobinostat and bortezomib
Arm Description
Oral Panobinostat and intravenous bortezomib
Outcomes
Primary Outcome Measures
Objective Response Rate
Secondary Outcome Measures
Time to response, Duration of response, Progression-free survival, Overall survival, Safety and tolerability, Changes in disease-related symptoms and ECOG performance status.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00901147
Brief Title
Study of Bortezomib and Panobinostat in Treating Patients With Relapsed/Refractory Peripheral T-cell Lymphoma or NK/T-cell Lymphoma
Official Title
An Open-label Phase 2 Study of Intravenous Bortezomib and Oral Panobinostat (LBH589) in Adult Patients With Relapsed/Refractory Peripheral T-cell Lymphoma or NK/T-cell Lymphoma After Failure of Conventional Chemotherapy
Study Type
Interventional
2. Study Status
Record Verification Date
June 2014
Overall Recruitment Status
Completed
Study Start Date
November 2009 (undefined)
Primary Completion Date
January 2014 (Actual)
Study Completion Date
January 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Singapore General Hospital
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
Keywords
t-cell lymphoma, peripheral t-cell lymphoma, nk/t-cell lymphoma, nasal type, bortezomib, velcade, panobinostat, LBH589b, histone deacetylase inhibitor, proteasome inhibitor
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
25 (Actual)
8. Arms, Groups, and Interventions
Arm Title
panobinostat and bortezomib
Arm Type
Experimental
Arm Description
Oral Panobinostat and intravenous bortezomib
Intervention Type
Drug
Intervention Name(s)
panobinostat and bortezomib
Other Intervention Name(s)
LBH589B, Velcade
Intervention Description
oral panobinostat 30 mg 3 times per week AND intravenous bortezomib 1.3mg/m2 on days 1,4,8,11 per cycle
Primary Outcome Measure Information:
Title
Objective Response Rate
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Time to response, Duration of response, Progression-free survival, Overall survival, Safety and tolerability, Changes in disease-related symptoms and ECOG performance status.
Time Frame
1 year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
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
Serum potassium ≥3.8 mmol/L and magnesium ≥0.85 mmol/L (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria)
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.
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;
Serum potassium <3.8 mmol/L or serum magnesium <0.85 mmol/L (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria)
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yeow Tee Goh, MBBS MMed
Organizational Affiliation
Singapore General Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Darryl Tan, MBBS MMED
Organizational Affiliation
Singapore General Hospital
Official's Role
Study Chair
Facility Information:
Facility Name
Samsung Medical Centre
City
Seoul
ZIP/Postal Code
135-710
Country
Korea, Republic of
Facility Name
Subang Jaya Medical Centre
City
Subang Jaya
State/Province
Selangor
ZIP/Postal Code
47500
Country
Malaysia
Facility Name
Hospital Universiti Kebangsaan Malaysia ( HUKM )
City
Kuala Lumpur
ZIP/Postal Code
56000
Country
Malaysia
Facility Name
National Cancer Center
City
Singapore
ZIP/Postal Code
169608
Country
Singapore
Facility Name
Singapore General Hospital
City
Singapore
ZIP/Postal Code
169608
Country
Singapore
12. IPD Sharing Statement
Citations:
PubMed Identifier
26688485
Citation
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.
Results Reference
derived
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Study of Bortezomib and Panobinostat in Treating Patients With Relapsed/Refractory Peripheral T-cell Lymphoma or NK/T-cell Lymphoma
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