Vorinostat, Bortezomib and Dexamethasone in Multiple Myeloma (MUKFour)

Phase 2

Completed

• Conditions: Multiple Myeloma
• Interventions: Drug: Vorinostat Velcade Dexamethasone

• Registration Number: NCT01720875
• Lead Sponsor: University of Leeds

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2012-10-31
• Study First Submitted QC: 2012-11-01
• Study First Posted: 2012-11-02
• Study Start: 2013-08-09
• Primary Completion: 2015-08
• Study Completion: 2018-08-29
• Status Verified: 2021-08
• Last Update Submitted: 2021-08-09
• Last Update Posted: 2021-08-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Vorinostat Velcade Dexamethasone (VVD)	Vorinostat Velcade Dexamethasone	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

Primary Outcome Measures

Name	Time	Method
Overall response rate to vorinostat, bortezomib and dexamethasone.	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

Name	Time	Method
Number of dose reductions during treatment with vorinostat, bortezomib and dexamethasone.	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	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	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	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	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.

Trial Locations

Locations (2)

Nottingham University Hospital; 🇬🇧 Nottingham, Nottinghamshire, United Kingdom

University Hospital Southampton; 🇬🇧 Southampton, United Kingdom