Vorinostat, Bortezomib and Dexamethasone in Multiple Myeloma (MUKFour)

NCT01720875 | Completed Phase 2 DMC

• 3 other identifiers: HM11/10041ISRCTN085776022011-005361-20
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 2

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.

Conditions

Multiple Myeloma

Outcome Measures

Primary Outcomes (1)

• Overall response rate to vorinostat, bortezomib and dexamethasone.

  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.

  up to 24 weeks

Secondary Outcomes (5)

• Number of dose reductions during treatment with vorinostat, bortezomib and dexamethasone.

  up to 24 weeks

• Overall numbers and rates of adverse events

  Up to 18 months

• Progression free survival

  Up to 18 months

• Maximum response to treatment

  Up to 24 weeks

• Time to maximum response

  Up to 18 months

Other Outcomes (1)

• Matched pairs analysis

  Up to 24 months

Study Arms (1)

Vorinostat Velcade Dexamethasone (VVD)

EXPERIMENTAL

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

Interventions

Vorinostat Velcade Dexamethasone DRUG

Also known as: Bortezomib (velcade)

Vorinostat Velcade Dexamethasone (VVD)

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Leeds: lead
• Myeloma UK: collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (2)

Nottingham University Hospital

Nottingham, Nottinghamshire, NG5 1PB, United Kingdom

Location

University Hospital Southampton

Southampton, SO16 6YD, United Kingdom

Location

Related Publications (1)

• Brown S, Pawlyn C, Tillotson AL, Sherratt D, Flanagan L, Low E, Morgan GJ, Williams C, Kaiser M, Davies FE, Jenner MW; Myeloma UK Early Phase Clinical Trial Network. Bortezomib, Vorinostat, and Dexamethasone Combination Therapy in Relapsed Myeloma: Results of the Phase 2 MUK four Trial. Clin Lymphoma Myeloma Leuk. 2021 Mar;21(3):154-161.e3. doi: 10.1016/j.clml.2020.11.019. Epub 2020 Dec 3.

  PMID: 33478922 RESULT

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Bortezomib

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

Study Officials

• Matthew Jenner

  University Hospital of Southampton

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2012
• First Posted: November 2, 2012
• Study Start: August 9, 2013
• Primary Completion: August 1, 2015
• Study Completion: August 29, 2018
• Last Updated: August 16, 2021

Record last verified: 2021-08

Locations

GB (2)