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

NCT02145715 | Unknown Phase 1 DMC

• 1 other identifier: HM12/10174
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 5

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

Outcome Measures

Primary Outcomes (2)

• Dose limiting toxicities (DLTs)

  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.

  From cycle 1 day 1 up to the administration of cycle 2 day 1 (up to 22 days)

• Proportion o f participants achieving at least partial response

  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

  within 16 cycles of therapy (an expected average of 48 weeks)

Secondary Outcomes (8)

• 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)

Study Arms (1)

Velcade, Thalidomide, Dexamethasone (VTD) + Panobinostat

EXPERIMENTAL

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

Drug: Velcade; Drug: Thalidomide; Drug: Dexamethasone; Drug: Panobinostat

Interventions

Velcade DRUG

Also known as: Bortezomib

Velcade, Thalidomide, Dexamethasone (VTD) + Panobinostat

Thalidomide DRUG

Velcade, Thalidomide, Dexamethasone (VTD) + Panobinostat

Dexamethasone DRUG

Velcade, Thalidomide, Dexamethasone (VTD) + Panobinostat

Panobinostat DRUG

Velcade, Thalidomide, Dexamethasone (VTD) + Panobinostat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Prof Jamie Cavenagh: lead
• Myeloma UK: collaborator
• Novartis: collaborator

Study Sites (5)

Birmingham Heartlands Hospital

Birmingham, UK, B9 5SS, United Kingdom

Location

Royal Liverpool University Hospital

Liverpool, L7 8XP, United Kingdom

Location

St Bartholomew's Hospital

London, EC1A 7BE, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, WC1E 6AG, United Kingdom

Location

Guy's Hospital

London, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 27843120 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Bortezomib; Thalidomide; Dexamethasone; Panobinostat

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Piperidones; Piperidines; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Hydroxamic Acids; Hydroxylamines; Amines; Hydroxy Acids; Indoles

Study Officials

• Jamie Cavenagh, MRCPath

  St. Bartholomew's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Chief Investigator

Study Record Dates

• First Submitted: March 1, 2013
• First Posted: May 23, 2014
• Study Start: January 1, 2013
• Primary Completion: July 1, 2015
• Study Completion: January 1, 2016
• Last Updated: June 26, 2015

Record last verified: 2015-06

Locations

GB (5)