Trial document




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  DRKS00003074

Trial Description

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Title

Safety of Vorinostat in combination with Bortezomib, Doxorubicin and
Dexamethasone (VBDD) in patients with refractory or relapsed multiple myeloma.
A phase I/II study

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Trial Acronym

VBDD

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URL of the Trial

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Brief Summary in Lay Language

Patients who suffer from multiple myeloma (MM) and received at least one prior MM therapy and whose disease progressed may be eligible to be treated in this study. The primary goal of the study is to assess the highest dose of Vorinostat (V) with 100mg, 200mg or 300mg), given in combination with fixed doses of Doxorubicin (D), Bortezomib (B) and Dexamethasone (D) with still acceptable side effects for the treated patient (=Maximal Tolerated Dose, MTD) (Phase I part). When the MTD is determined, additional patients may be enrolled and treated with VBDD (Phase II part).
In the final evaluation, data in regard to response rates, duration of response, progression-free and overall survival, safety of the VBDD therapy, patient´s quality of life before and after VBDD treatment, will be assessed. Furthermore, the effect of vorinostat on the plasma cells in patient´s blood and bone marrow samples will be investigated in the laboratory.

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Brief Summary in Scientific Language

Prospective, open, non-randomized, non-controlled, monocenter, phase I/II clinical study with a consecutive 3 to 3 group design. 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 objectives are:
Assessment of safety and tolerability of VBDD; efficacy data of VBDD.

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Organizational Data

  •   DRKS00003074
  •   2011/07/07
  •   2011/07/13
  •   yes
  •   Approved
  •   98/11, Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
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Secondary IDs

  •   2011-000388-28 
  •   NCT01394354  (clinicaltrials.gov)
  •   4037198 
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Health Condition or Problem studied

  •   C90.0 -  Multiple myeloma
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Interventions/Observational Groups

  •   Vorinostat 100 mg/d, on 12 days in combination with BDD in a 28-d-cycle.
    The dose level of Vorinostat will be escalated in each new cohort if no dose limiting toxicity (DLT) occurs to 200 mg/d and 300 mg/d.
    Bortezomib will be administered intravenously (i.v.) 1.3mg/m2 on 3 days in a 28-d-cycle.
    Doxorubicin will be administered i.v. with a total dose of 18 mg/m2 per cycle.
    Dexamethasone will be administered per os (p.o.) with 40mg (first cycle) and 20mg (all other subsequent cycles) on 4 days in a 28-d-cycle.
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   I-II
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Primary Outcome

Maximum tolerated dose (MTD) of Vorinostat, given in combination with fixed doses of Doxorubicin, Bortezomib and Dexamethasone.
The primary target variable is the occurrence of any dose-limiting toxicity (DLT) in MM patients during the first 28 days of treatment.

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Secondary Outcome

• Response rates: complete remission (CR, including stringent CR [sCR]), very good partial response (vgPR), partial remission (PR), stable disease (SD), progressive disease (PD)
• Duration of response in all 3 groups (level 0 vs. 1 vs. 2) with VBDD
• Progression-free (PFS) and overall survival (OS)
• Safety
• Specific myeloma prognostic parameters
• Quality of Life before and after VBDD treatment

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2011/09/20
  •   45
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional 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

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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
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

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Addresses

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    • Universitätsklinikum Freiburg - vertreten durch den Leitenden Ärztlichen Direktor - Prof. Dr. Dr. h.c. J. R. Siewert
    • Hugstetter Str. 49
    • 79106   Freiburg
    • Germany
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    • Universitätsklinikum Freiburg, Innere Med. I, Hämatologie und Onkologie
    • Ms.  Dr. rer. nat.   Ulrike   Kohlweyer 
    • Hugstetter Str. 55
    • 79106   Freiburg
    • Germany
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    • Universitätsklinikum Freiburg Abt. Innere Med. I, Hämatologie und Onkologie
    • Ms.  Prof. Dr. med.  Monika  Engelhardt 
    • Hugstetter Str. 55
    • 79106  Freiburg
    • Germany
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Sources of Monetary or Material Support

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    • MSD Sharp & Dohme GmbH
    • 85540  Haar
    • Germany
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    • Janssen-Cilag GmbH
    • 41470  Neuss
    • Germany
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Status

  •   Recruiting complete, follow-up continuing
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Trial Publications, Results and other Documents

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