Clinical trial NCT01720875: Vorinostat, Bortezomib and Dexamethasone in Multiple Myeloma (MUKFour)
Official title: A Phase II Trial of Combination Treatment With Vorinostat, Bortezomib and Dexamethasone in Patients With Relapsed and Relapsed Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Lead sponsor: University of Leeds
Sponsor class: OTHER
Collaborators: name: Myeloma UK
name: Merck Sharp & Dohme LLC
First posted: 2012-11-02
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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)

Primary outcomes:
measure: Overall response rate to vorinostat, bortezomib and dexamethasone.
timeFrame: up to 24 weeks
Secondary outcomes:
measure: Number of dose reductions during treatment with vorinostat, bortezomib and dexamethasone.
timeFrame: up to 24 weeks
measure: Overall numbers and rates of adverse events
timeFrame: Up to 18 months
measure: Progression free survival
timeFrame: Up to 18 months
measure: Maximum response to treatment
timeFrame: Up to 24 weeks
measure: Time to maximum response
timeFrame: Up to 18 months
Other outcomes:
measure: Matched pairs analysis
timeFrame: Up to 24 months
Locations:
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospital
state: Nottinghamshire
city: Southampton
country: United Kingdom
facility: University Hospital Southampton
Study officials:
affiliation: University Hospital of Southampton
name: Matthew Jenner
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.