Velcade, Thalidomide, Dexamethasone and Panobinostat Treatment and Panobinostat Maintenance in Multiple Myeloma

NCT ID: NCT02145715

Last Updated: 2015-06-26

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 54 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-01-31
• Study Completion Date: 2016-01-31

Brief Summary

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.

Conditions

Multiple Myeloma

Study Design

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

Study Groups

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

Group Type: EXPERIMENTAL

Velcade

Intervention Type: DRUG

Thalidomide

Intervention Type: DRUG

Dexamethasone

Intervention Type: DRUG

Panobinostat

Intervention Type: DRUG

Interventions

Velcade

Intervention Type: DRUG

Thalidomide

Intervention Type: DRUG

Dexamethasone

Intervention Type: DRUG

Panobinostat

Intervention Type: DRUG

Other Intervention Names

Bortezomib

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Myeloma UK

OTHER

Sponsor Role: collaborator

Novartis

INDUSTRY

Sponsor Role: collaborator

Prof Jamie Cavenagh

OTHER

Sponsor Role: lead

Responsible Party

Prof Jamie Cavenagh

Chief Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Jamie Cavenagh, MRCPath

Role: PRINCIPAL_INVESTIGATOR

St. Bartholomew's Hospital

Locations

Birmingham Heartlands Hospital

Birmingham, UK, United Kingdom

Royal Liverpool University Hospital

Liverpool, , United Kingdom

St Bartholomew's Hospital

London, , United Kingdom

University College London Hospitals NHS Foundation Trust

London, , United Kingdom

Guy's Hospital

London, , United Kingdom

Countries

United Kingdom

References

Popat R, Brown SR, Flanagan L, Hall A, Gregory W, Kishore B, Streetly M, Oakervee H, Yong K, Cook G, Low E, Cavenagh J; Myeloma UK Early Phase Clinical Trial Network. Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial. Lancet Haematol. 2016 Dec;3(12):e572-e580. doi: 10.1016/S2352-3026(16)30165-X. Epub 2016 Nov 12.

Reference Type: DERIVED

PMID: 27843120 (View on PubMed)

Other Identifiers

HM12/10174

Identifier Type: -

Identifier Source: org_study_id