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Vorinostat, Bortezomib and Dexamethasone in Multiple Myeloma (MUKfour)

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified October 2012 by University of Leeds.
Recruitment status was:  Not yet recruiting
Information provided by:
University of Leeds Identifier:
First received: October 31, 2012
Last updated: November 1, 2012
Last verified: October 2012

Bortezomib is an established treatment in multiple myeloma; it is common practice in the UK to administer bortezomib with dexamethasone. This practice is based on data that supports improved response rates with this combination.

Recent trial data indicates that the addition of vorinostat to bortezomib treatment overcomes treatment resistance to bortezomib. As such this current trial is designed to investigate the efficacy, safety and tolerability of combination treatment with vorinostat, bortezomib and dexamethasone in patients with relapsed and relapsed refractory myeloma.

A comparison of this Phase II trial with the pivotal Phase III trial conducted by MSD (using the labelled bortezomib indication without dexamethasone) will address the impact of dexamethasone in regards to tolerability and additional efficacy in myeloma patients.

Condition Intervention Phase
Multiple Myeloma
Drug: Vorinostat Velcade Dexamethasone
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial of Combination Treatment With Vorinostat, Bortezomib and Dexamethasone in Patients With Relapsed and Relapsed Refractory Multiple Myeloma

Resource links provided by NLM:

Further study details as provided by University of Leeds:

Primary Outcome Measures:
  • Overall response rate to vorinostat, bortezomib and dexamethasone. [ Time Frame: up to 24 weeks ]
    To assess the number and proportion of participants with at least a partial response (PR) or better within 8 cycles of protocol treatment with vorinostat, bortezomib and dexamethasone.

Secondary Outcome Measures:
  • Number of dose reductions during treatment with vorinostat, bortezomib and dexamethasone. [ Time Frame: up to 24 weeks ]
    To assess the dose reduction profile of combination treatment with vorinostat, bortezomib and dexamethasone. The proportion of participants experiencing a dose reduction or terminating treatment early due to toxicity will be assessed.

  • Overall numbers and rates of adverse events [ Time Frame: Up to 18 months ]
    Safety and toxicity analyses will summarise the overall serious adverse event and adverse events rates including the number and proportion of participants with at least one safety event. SAEs will be additionally presented by the relationship to study treatment, seriousness criteria, event outcome, duration and by MedDRA body system coding.

  • Progression free survival [ Time Frame: Up to 18 months ]
    A progression-free survival curve will be calculated using the Kaplan Meier method and median PFS estimates will be presented

  • Maximum response to treatment [ Time Frame: Up to 24 weeks ]
    The overall number and proportion of participants in each response category within 8 cycles of treatment and overall across all treatment including the maintenance phase

  • Time to maximum response [ Time Frame: Up to 18 months ]
    The time to maximum response will be calculated from the date of registration to the date of maximum response. Participant's who progress and do not achieve a maximum response will be censored at the time of progression. Median time to maximum response will be presented.

Other Outcome Measures:
  • Matched pairs analysis [ Time Frame: Up to 24 months ]
    A matched pairs analysis will be carried out looking at overall response, PFS, dose reductions and toxicity in participants treated with vorinostat in combination with bortezomib and dexamethasone (VVD) in this current study compared to participants randomised to the bortezomib/vorinostat (VV) arm in the pivotal MSD phase III study.

Estimated Enrollment: 68
Study Start Date: March 2013
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vorinostat Velcade Dexamethasone (VVD)

Up to 8 cycles of VVD followed by vorinostat maintenance until disease progression.

Cycles 1-8 (21-day cycle)

  • Velcade: 1.3mg/m2 (subcutaneous) on days 1, 4, 8 and 11
  • Dexamethasone: 20 mg (PO) on days 1, 2, 4, 5, 8, 9, 11 and 12
  • Vorinostat: 400mg (PO) on days 1-4, 8-11, 15-18 Maintenance (28-day cycle)
  • Vorinostat: 400mg PO on 1-4 and 15-18
Drug: Vorinostat Velcade Dexamethasone
Other Name: Bortezomib (velcade)


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Able to give informed consent - Aged 18 years or over
  • Participants with relapsed myeloma who have received 1-3 prior lines of treatment and now require further treatment
  • ECOG Performance Status ≤ 2
  • Required laboratory values within 14 days of registration:

    • Absolute neutrophil count ≥1.0 x 10^9/L.
    • Platelet count ≥75x10^9/L.
    • Haemoglobin > 9 g/dL.
    • Bilirubin ≤1.5 x upper limit of normal
    • ALT and / or AST ≤2.5 x upper limit of normal
    • Serum creatinine ≤ 2.0 x upper limit of normal
    • Corrected calcium ≤ 2.8 mmol/L
  • Life expectancy of at least 3 months
  • Female participants 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 participants 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
  • Participant is able to swallow capsules and is able to take or tolerate oral medications on a continuous basis.

Exclusion Criteria:

  • 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 to stop rapid relapse during this period is permitted, but must be stopped 7 days prior to study drug administration.
  • Prior HDAC inhibitor treatment.
  • Previous or concurrent active malignancies (<12 months post end of treatment) at other sites with the exception of appropriately treated localised epithelial skin or cervical cancer.
  • Participants considered to be refractory to prior bortezomib treatment or unable to tolerate treatment with bortezomib.
  • Peripheral neuropathy of ≥ grade 2 severity
  • Participants who have received growth factor support or platelet support within 14 days prior to registration
  • Participants with uncontrolled concurrent illness or circumstances that could limit compliance with the study.
  • Patients with significant cardiovascular or pulmonary disease
  • Active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B, or C) hepatitis.
  • Pregnant or breast feeding females
  • Unable to take corticosteroid therapy at study entry
  • Participants with known hypersensitivity to any components of bortezomib, (such as boron, mannitol), vorinostat or dexamethasone.
  • Participant has known CNS metastases and/or carcinomatous meningitis.
  • Participants with a history of a gastrointestinal surgery or other procedures that might, in the opinion of the Investigator, interfere with the absorption or swallowing of the study drug(s)
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Please refer to this study by its identifier: NCT01720875

Contact: Louise M Flanagan, BSc PhD +44 113 343 6441

United Kingdom
Nottingham University Hospital
Nottingham, Nottinghamshire, United Kingdom, NG5 1PB
Royal Marsden NHS Foundation Trust
London, United Kingdom, SM2 5PT
Sponsors and Collaborators
University of Leeds
Principal Investigator: Faith Davies, MRCPath Institute of Cancer Research, United Kingdom
  More Information Identifier: NCT01720875     History of Changes
Other Study ID Numbers: HM11/10041
ISRCTN08577602 ( Registry Identifier: ISRCTN )
2011-005361-20 ( EudraCT Number )
Study First Received: October 31, 2012
Last Updated: November 1, 2012

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone 21-phosphate
BB 1101
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal processed this record on April 28, 2017