Clinical trial NCT02145715: Velcade, Thalidomide, Dexamethasone and Panobinostat Treatment and Panobinostat Maintenance in Multiple Myeloma
Official title: A Phase I/IIa Trial of VTD-panobinostat Treatment and Panobinostat Maintenance in Relapsed and Relapsed/Refractory Multiple Myeloma Patients
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Lead sponsor: University of Leeds
Sponsor class: OTHER
Collaborators: name: Myeloma UK
name: Novartis
First posted: 2014-05-23
Enrollment: 54
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: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Dose limiting toxicities (DLTs)
timeFrame: From cycle 1 day 1 up to the administration of cycle 2 day 1 (up to 22 days)
measure: Proportion o f participants achieving at least partial response
timeFrame: within 16 cycles of therapy (an expected average of 48 weeks)
Secondary outcomes:
measure: Safety and toxicity
timeFrame: Throughout the trial, expected to be 3 years
measure: Proportion of patients with each maximum response category
timeFrame: within 16 cycles of therapy (an expected average of 48 weeks)
measure: Time to maximum response to therapy
timeFrame: 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)
measure: Progression free survival
timeFrame: from registration to first documented evidence of disease progression or death (up to 100 weeks)
measure: Compliance to therapy
timeFrame: from initial treatment received as per protocol until treatment withdrawal (up to 100 weeks)
measure: Feasibility of panobinostat maintenance
timeFrame: up to 12 months
measure: Overall survival
timeFrame: from registration to date of death
measure: The proportion of participants mobilising sufficient stem cells for transplant(out of those undergoing mobilisation)
timeFrame: up to 16 cycles of therapy (an expected average of 48 weeks)
Other outcomes:
Locations:
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: UK
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Guy's Hospital
Study officials:
affiliation: St. Bartholomew's Hospital
name: Jamie Cavenagh, MRCPath
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.