A Phase I/IIa Trial of VTD-panobinostat Treatment and Panobinostat Maintenance in Relapsed and Relapsed/Refractory Multiple Myeloma Patients
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 54
- 试验地点
- 5
- 主要终点
- Dose limiting toxicities (DLTs)
研究概览
简要总结
Velcade (bortezomib), thalidomide and dexamethasone (VTD) has been demonstrated to be a highly effective combination in both patients with previously untreated and those with relapsed multiple myeloma. In previously untreated patients VTD demonstrated clear superiority to TD as induction therapy prior to planned tandem autologous stem cell transplant.
The rationale of this trial is to combine a 'gold standard' antiMM combination with the HDAC inhibitor Panobinostat. There is emerging data to support the concept of clinical synergy between BTZ and HDACi's.
The purpose of this study is to determine the maximum tolerated dose (MTD) and estimated response rates of panobinostat, administered in combination with VTD, in subjects with relapsed and relapsed/refractory multiple myeloma.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with a previous diagnosis of multiple myeloma based on IMWG 2003 definitions:
- •Monoclonal immunoglobulin (M component) on electrophoresis, and on immunofixation of serum or of total 24 hour urine
- •Bone marrow (clonal) plasma cells ≥ 10% or biopsy proven plasmacytoma
- •Related organ or tissue impairment (CRAB symptoms, anemia, hypercalcemia, lytic bone lesions, renal insufficiency, hyperviscosity, amyloidosis or recurrent infections)
- •Relapsed and relapsed-and-refractory myeloma who have received 1-4 prior lines and now require further treatment
- •Able to give informed consent and willing to follow study protocol
- •Aged 18 years or over
- •ECOG Performance Status ≤2
- •Required laboratory values within 14 days of registration:
- •Absolute neutrophil count ≥1.0 x 109/L.
- •Platelet count ≥100 x 109/L.
- •Haemoglobin ≥8.0g/dL.
- •Bilirubin ≤2 upper limit of normal (ULN)
- •AST and/or ALT ≤2.5 ULN; except in subjects with known hepatic involvement, where AST and/or ALT ≤5.0 ULN
- •Serum creatinine ≤2.0 ULN
- •Corrected calcium ≤2.8 mmol/L.
- •Anticipated survival of at least 3 months
- •Evaluable disease per modified IWG criteria, utilising the following assessments as appropriate:
- •Serum M protein ≥ 10g/l.
- •Urine M protein ≥ 200mg/24 hours
- •Serum free light chain assay: involved FLC level ≥ 100mg/l. Provided serum FLC ratio is abnormal
- •Female subjects of child-bearing potential must have a negative pregnancy test at baseline and agree to use dual methods of contraception for the duration of the study and must continue to do so for 3 months after the end of treatment. Male subjects must agree to use a barrier method of contraception for the duration of the study if sexually active with a female of child-bearing potential and must continue to do so for 3 months after the end of treatment.
排除标准
- •Pregnant (positive pregnancy test) or breastfeeding women.
- •Non-secretory Multiple Myeloma Previous anti-tumour therapies, including prior experimental agents or approved anti-tumour small molecules and biologics, within 28 days before the start of protocol treatment. Steroid therapy is permitted (maximum 160 mg dexamethasone or equivalent), but must be stopped 48 hours prior to study drug administration. Bisphosphonates for bone disease and radiotherapy for palliative intent are also permitted.
- •Concurrent or previous malignancies (<12 months post end of treatment) at other sites with the exception of appropriately treated localised epithelial skin or cervical cancer, or incidental histologic findings of prostate cancer (TMN stage T1a or 1b). Patients with histories (≥12 months) of other tumours may be entered.
- •Poorly controlled or serious medical or psychiatric illness that, in the Investigator's opinion, is likely to interfere with participation and/or compliance in this clinical study
- •Patients with significant cardiovascular disease (e.g. history of congestive heart failure requiring therapy, presence of severe valvular heart disease, presence of an atrial or ventricular arrhythmia requiring treatment, uncontrolled hypertension, a history of clinically significant QTc abnormalities)
- •Active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B, or C) hepatitis.
- •Gastrointestinal disorders that may interfere with absorption of the study drug
- •Patients who have been refractory to prior bortezomib, i.e. did not achieve at least an MR, or who have progressed on therapy or within 60 days of last dose
- •Participants with peripheral neuropathy CTC grade 2 or higher or grade 1 with pain within 14 days prior to registration
- •Any history or known hypersensitivity to any of the study medications or excipients
研究组 & 干预措施
Velcade, Thalidomide, Dexamethasone (VTD) + Panobinostat
Up to 16 cycles of VTD+Panobinostat followed by panobinostat maintenance for 1 year or until disease progression.
-
Induction - Cycles 1-16 (21-day cycle)
-
Velcade: 1.3mg/m2 (subcutaneous) on days 1 and 8
-
Thalidomide: 100mg (PO)on days 1 -21
-
Dexamethasone: 20 mg (PO) on days 1, 2, 8 and 9
-
Panobinostat: 10mg, 15mg or 20mg days 1, 3, 5, 8, 10 and 12 Dose depends on cohort entry at registration during the dose escalation phase. The recommended dose will be used during the expansion phase.
-
Panobinostat monotherapy maintenance for 1 year. Panobinostat will be given at the same dose as the recommended dose during expansion phase
干预措施: Velcade (Drug)
Velcade, Thalidomide, Dexamethasone (VTD) + Panobinostat
Up to 16 cycles of VTD+Panobinostat followed by panobinostat maintenance for 1 year or until disease progression.
-
Induction - Cycles 1-16 (21-day cycle)
-
Velcade: 1.3mg/m2 (subcutaneous) on days 1 and 8
-
Thalidomide: 100mg (PO)on days 1 -21
-
Dexamethasone: 20 mg (PO) on days 1, 2, 8 and 9
-
Panobinostat: 10mg, 15mg or 20mg days 1, 3, 5, 8, 10 and 12 Dose depends on cohort entry at registration during the dose escalation phase. The recommended dose will be used during the expansion phase.
-
Panobinostat monotherapy maintenance for 1 year. Panobinostat will be given at the same dose as the recommended dose during expansion phase
干预措施: Thalidomide (Drug)
Velcade, Thalidomide, Dexamethasone (VTD) + Panobinostat
Up to 16 cycles of VTD+Panobinostat followed by panobinostat maintenance for 1 year or until disease progression.
-
Induction - Cycles 1-16 (21-day cycle)
-
Velcade: 1.3mg/m2 (subcutaneous) on days 1 and 8
-
Thalidomide: 100mg (PO)on days 1 -21
-
Dexamethasone: 20 mg (PO) on days 1, 2, 8 and 9
-
Panobinostat: 10mg, 15mg or 20mg days 1, 3, 5, 8, 10 and 12 Dose depends on cohort entry at registration during the dose escalation phase. The recommended dose will be used during the expansion phase.
-
Panobinostat monotherapy maintenance for 1 year. Panobinostat will be given at the same dose as the recommended dose during expansion phase
干预措施: Dexamethasone (Drug)
Velcade, Thalidomide, Dexamethasone (VTD) + Panobinostat
Up to 16 cycles of VTD+Panobinostat followed by panobinostat maintenance for 1 year or until disease progression.
-
Induction - Cycles 1-16 (21-day cycle)
-
Velcade: 1.3mg/m2 (subcutaneous) on days 1 and 8
-
Thalidomide: 100mg (PO)on days 1 -21
-
Dexamethasone: 20 mg (PO) on days 1, 2, 8 and 9
-
Panobinostat: 10mg, 15mg or 20mg days 1, 3, 5, 8, 10 and 12 Dose depends on cohort entry at registration during the dose escalation phase. The recommended dose will be used during the expansion phase.
-
Panobinostat monotherapy maintenance for 1 year. Panobinostat will be given at the same dose as the recommended dose during expansion phase
干预措施: Panobinostat (Drug)
结局指标
主要结局
Dose limiting toxicities (DLTs)
时间窗: From cycle 1 day 1 up to the administration of cycle 2 day 1 (up to 22 days)
The number of participants experiencing DLTs within the first cycle of VTD-pano will be presented, with descriptive summaries of the specific DLTs observed. Summaries will be presented for each dose level.
Proportion o f participants achieving at least partial response
时间窗: within 16 cycles of therapy (an expected average of 48 weeks)
The proportion of participants achieving at least a partial response within 16 cycles of VTD-pano will be presented, with corresponding 80% and 95% confidence intervals
次要结局
- Safety and toxicity(Throughout the trial, expected to be 3 years)
- Proportion of patients with each maximum response category(within 16 cycles of therapy (an expected average of 48 weeks))
- Time to maximum response to therapy(from registration until the participant achieves any of the categories CR, VGPR, PR, MR or SD as their maximum response (up to 100 weeks - 48 weeks of treatment plus 52 weeks maintenance))
- Progression free survival(from registration to first documented evidence of disease progression or death (up to 100 weeks))
- Compliance to therapy(from initial treatment received as per protocol until treatment withdrawal (up to 100 weeks))
- Feasibility of panobinostat maintenance(up to 12 months)
- Overall survival(from registration to date of death)
- The proportion of participants mobilising sufficient stem cells for transplant(out of those undergoing mobilisation)(up to 16 cycles of therapy (an expected average of 48 weeks))
研究者
Prof Jamie Cavenagh
Chief Investigator
University of Leeds