Safety of Vorinostat in combination with Bortezomib, Doxorubicin and Dexamethasone (VBDD) in patients with refractory or relapsed multiple myeloma

Conditions: Relapsed or refractory multiple myeloma
MedDRA version: 18.0Level: LLTClassification code 10028228Term: Multiple myelomaSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2011-000388-28-DE

Lead Sponsor: niversity Medical Center Freiburg

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: Not specified

Inclusion Criteria

1.Patient has voluntarily agreed to participate, understands and voluntarily signed a written informed consent form
2.Male or female patients with age =18 years without upper age limit
3.Patients with refractory or relapsed MM after at least first-line chemotherapy (CTx) or PBSCT (autologous and allogeneic SCT). All lines of relapse are eligible.
4.Measurable disease, defined as any quantifiable serum M-protein value OR in light-chain-MM elevated measurable serum free light chains OR in non-secretory MM measurable disease in terms of extramedullary sites and/or Bone marrow (BM) plasmocytosis >10%, 24-h-urine M-protein
5.Non-secretory disease allowed, provided magnetic resonance imaging (MRI) or positron emission tomography (PET) or computed tomography (CT) scan can accurately measure at least one plasmocytoma lesion and/or BM-plasmocytosis allows to determine response
6.Patient must be at least 30 days from prior CTx, radiation therapy, biological therapy, immunotherapy, major surgery or any other investigational anticancer therapy prior to the first dose of study drugs.
7.KPS =60%
8.Normal serum potassium and magnesium
9.Adequate BM function (ANC =1000/mm3, platelet count =50.000/mm3, Hb >7 g/dl, unless myelosuppression is secondary to BM plasmocytosis >70% involvement)
10.Adequate hepatic and renal function (AST and ALT =2.5 times ULN, Bilirubin =1.5 times ULN, eGFR >20 ml/min)
11.Patient is able to swallow pills/oral medication

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 15
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 30

Exclusion Criteria

1.Patient has had prior treatment with Vorinostat or HDAC inhibitors
2.Patient has previously been unable to tolerate prior treatment with Bortezomib, Doxorubicin (or other anthracyclines) or Dexamethasone, or has a known hypersensitivity to any components of Bortezomib, Doxorubicin, Vorinostat or Dexamethasone
3.Previous treatment above maximum cumulative doses of doxorubicin (> 550mg/m2), daunorubicin (> 550mg/m2), epirubicin (> 900mg/m2), idarubicin (> 120mg/m2), and/or other anthracyclines.
4.Patients with severe hepatic impairment or acute diffuse infiltrative pulmonary and pericardial disease, or any of the following: marked myelosuppression; pre-existing heart disease (severe heart failure (ejection fraction [EF]< 30%); acute or history of myocardial infarction, severe arrhythmias, acute inflammatory cardiac disease), inflammation of mucous membranes, hemorrhagic diathesis, established generalised infections.
5.Patients with other active severe illness, including patient is known to be Human Immunodeficiency Virus (HIV) positive or has clinically active Hepatitis B or C.
6.Patient has preexisting NCI CTC =grade 3 neuropathy.
7.Patient with known CNS MM-involvement and/or MM-related/induced meningitis
8.Concomitant use of any other investigational drug or participation in a clinical trial within the last thirty days before the start of this study, previous participation in this study
9.Known or persistent abuse of medication, drugs or alcohol
10.In case of a patient without legal capacity who is unable to understand the nature, significance and consequences of the study, a legal representative has to give and sign the patient informed consent form.
11.Persons who are in a relationship of dependence/employment with the sponsor or the investigator
12.Female patients with current or planned pregnancy or during nursing period
13.Fertile patients refusing to use safe contraceptive methods (at least two) during the study until six months after the final administration of the study medication (for details see clinical trial protocol section 5.3).

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Primary objective of the study is the determination of the maximum tolerated dose (MTD) of Vorinostat (V), given in combination with fixed doses of Doxorubicin (D), Bortezomib (B) and Dexamethasone (D).;Secondary Objective: Secondary objectives are: <br>Assessment of safety and tolerability of VBDD; efficacy data of VBDD<br>;Primary end point(s): •Maximum tolerated dose (MTD) of Vorinostat, given in combination with fixed doses of Doxorubicin, Bortezomib and Dexamethasone.<br>The primary target variable is the occurrence of any dose-limiting toxicity (DLT) in MM patients during the first 28 days of treatment.<br>;Timepoint(s) of evaluation of this end point: After the first 28 days of treatment

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): •Response rates: complete remission (CR, including stringent CR [sCR]), very good partial response (vgPR), partial remission (PR), stable disease (SD), progressive disease (PD)<br>•Duration of response in all 3 groups (level 0,1 vs. 2) with VBDD<br>•Progression-free (PFS) and overall survival (OS) <br>•Safety<br>•Specific myeloma prognostic parameters<br>•Quality of Life before and after VBDD treatment;Timepoint(s) of evaluation of this end point: At the end of the study

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