Velcade, Thalidomide, Dexamethasone and Panobinostat Treatment and Panobinostat Maintenance in Multiple Myeloma (MUKsix)

A Phase I/IIa Trial of VTD-panobinostat Treatment and Panobinostat Maintenance in Relapsed and Relapsed/Refractory Multiple Myeloma Patients

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.

Study Overview

• Status: Unknown
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Dexamethasone; Drug: Thalidomide; Drug: Velcade; Drug: Panobinostat

• Study Type: Interventional
• Enrollment (Anticipated): 54
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Liverpool, United Kingdom, L7 8XP
    • Royal Liverpool University Hospital
  • London, United Kingdom, EC1A 7BE
    • St Bartholomew's Hospital
  • London, United Kingdom
    • Guy's Hospital
  • London, United Kingdom, WC1E 6AG
    • University College London Hospitals Nhs Foundation Trust
  • UK
    • Birmingham, UK, United Kingdom, B9 5SS
      • Birmingham Heartlands Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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 8Thalidomide: 100mg (PO)on days 1 -21Dexamethasone: 20 mg (PO) on days 1, 2, 8 and 9Panobinostat: 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: Dexamethasone; Drug: Thalidomide; Drug: Velcade; Other Names: Bortezomib; Drug: Panobinostat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and toxicity	The proportion of participants experiencing DLTs and other toxicities, overall and by cycle as graded by CTCAE V4.0.	Throughout the trial, expected to be 3 years
Proportion of patients with each maximum response category	The number and proportion of participants in each response category within 16 cycles of VTD-pano will be presented with corresponding 95% confidence intervals.	within 16 cycles of therapy (an expected average of 48 weeks)
Time to maximum response to therapy	Time to maximum response is defined as the time from registration until the patient achieves any of the categories CR, VGPR, PR, MR or SD as their maximum response. Median time to maximum response will be presented.	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	A progression-free survival curve will be calculated using the Kaplan Meier method and median PFS estimates will be presented.	from registration to first documented evidence of disease progression or death (up to 100 weeks)
Compliance to therapy	Compliance to therapy will be summarised descriptively, including number of doses missed and number of dose reductions throughout the treatment period.	from initial treatment received as per protocol until treatment withdrawal (up to 100 weeks)
Feasibility of panobinostat maintenance	The duration of maintenance and reasons for stopping will be summarised	up to 12 months
Overall survival	Overall survival (OS) curves will be calculated using the Kaplan Meier method. Median OS, and OS estimates at 12 months, will be presented, if appropriate.	from registration to date of death
The proportion of participants mobilising sufficient stem cells for transplant(out of those undergoing mobilisation)	To be determined by the satisfactory collection of sufficient numbers of stem cells to support high-dose chemotherapy.	up to 16 cycles of therapy (an expected average of 48 weeks)

Collaborators and Investigators

• Sponsor: Prof Jamie Cavenagh
• Collaborators: Novartis; Myeloma UK
• Investigators: Principal Investigator: Jamie Cavenagh, MRCPath, St. Bartholomew's Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Anticipated): July 1, 2015
• Study Completion (Anticipated): January 1, 2016

Study Registration Dates

• First Submitted: March 1, 2013
• First Submitted That Met QC Criteria: May 20, 2014
• First Posted (Estimate): May 23, 2014

Study Record Updates

• Last Update Posted (Estimate): June 26, 2015
• Last Update Submitted That Met QC Criteria: June 25, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Histone Deacetylase Inhibitors; Dexamethasone; Thalidomide; Bortezomib; Panobinostat
• Other Study ID Numbers: HM12/10174