Vorinostat in Combination With Bortezomib, Doxorubicin and Dexamethasone (VBDD) in Patients With Refractory or Relapsed Multiple Myeloma (MM)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by University Hospital Freiburg
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Janssen-Cilag Ltd.
Information provided by (Responsible Party):
Monika Engelhardt, University Hospital Freiburg
ClinicalTrials.gov Identifier:
NCT01394354
First received: June 21, 2011
Last updated: June 27, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Multiple Myeloma in Relapse
Drug: Vorinostat
Drug: Bortezomib
Drug: Doxorubicin
Drug: Dexamethasone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official 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, Short Title: VBDD

Resource links provided by NLM:


Further study details as provided by University Hospital Freiburg:

Primary Outcome Measures:
  • Maximal Tolerated Dose (MTD) [ Time Frame: 28 days (within first treatment cycle) ] [ Designated as safety issue: Yes ]
    The Maximal Tolerated Dose (MTD) is estimated as the highest dose at which less than two DLTs in 6 patients are observed in the first cycle. MTD estimation is based on the phase I part of the trial. However, the number of DLT's in the first cycle of the phase II patients will be inspected and discussed as well. The primary target variable is the occurrence of any dose-limiting toxicity (DLT) in MM patients during the first 28 days of treatment.


Secondary Outcome Measures:
  • Response [ Time Frame: up to 1 year after inclusion of the last patient ] [ Designated as safety issue: Yes ]
    complete remission (CR, including stringent CR [sCR]), very good partial response (vgPR), partial remission (PR), stable disease (SD), progressive disease (PD). These parameters will be evaluated according to IMWG criteria.

  • Rates of Adverse Events (AE),Serious Adverse Events and AEs leading to permanent treatment discontinuation [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]

    throughout time of treatment (6 months) + 3 months after end of treatment (Follow-up).

    Rates of AE, Serious AE and AEs leading to permanent treatment discontinuation will be provided with accompanying 2-sided 95% confidence intervals. Safety parameters will be analyzed descriptively.

    An AE is any untoward medical occurrence in a patient administered any dose of VBDD study drugs and is defined in detail in the clinical trial protocol. An AE can be any unfavorable sign (incl. an abnormal lab and ECG-findings etc.), symptom, or disease related or not to the study drug.


  • Quality of Life [ Time Frame: during screening period (within 28 days) before start of treatment and at EOT (whether after the completion of the anticipated 6 cycles of chemotherapy or at an earlier time point if patient has to stop treatment because of clinical reasons) ] [ Designated as safety issue: No ]
    Assessment with Quality of Life-Questionnaire SF-12

  • Duration of Response [ Time Frame: up to one year after inclusion of the last patient ] [ Designated as safety issue: Yes ]
    Clinical assessment

  • Progression-free survival (PFS) [ Time Frame: up to 1 year after inclusion of the last patient ] [ Designated as safety issue: Yes ]
    estimation by using Kaplan-Meier method

  • Overall survival (OS) [ Time Frame: up to 1 year after inclusion of the last patient ] [ Designated as safety issue: Yes ]
    estimation by using Kaplan-Meier method


Estimated Enrollment: 30
Study Start Date: August 2011
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1

Vorinostat. To determine the MTD, dose escalation for Vorinostat will be conducted following the "3 + 3 design The first cohort of 3 patients will be given 100mg/d on days 1-4, 8-11, 15-18. The second cohort of 3 new patients will be treated with Vorinostat 200mg/d. The third cohort will be given Vorinostat 300mg/d. Cycles will be repeated every 28 days. Maximum treatment cycles: 6. Bortezomib will be administered intravenously (i.v.) 1.3mg/m2 BSA an days 1, 8, 15.

Doxorubicin will be administered i.v. with a total dose of 18mg/m2 BSA per cycle (9mg/m2 BSA, d1 and 8).

Dexamethasone will be administered per os (p.o.) with 40mg (first cycle) or 20mg (all other cycles) on d1, 8, 15, and 22.

Drug: Vorinostat

Vorinostat 100 mg/d p.o., on day 1-4, 8-11, and 15-18 /28 day treatment cycle in combination with BDD.

The dose level of Vorinostat will be escalated in each new cohort:

if no dose limiting toxicity (DLT) has been observed in the previous dose level in 3 patient, the second cohort of 3 new patients will be treated with Vorinostat 200 mg/d p.o. and the third cohort will be given Vorinostat with 300 mg/d p.o.

Other Name: ZOLINZA®, ATC code: L01XX
Drug: Bortezomib
1.3mg/m2 (days 1,8,15)/28 day treatment cycle, i.v., for max. 6 treatment cycles
Other Name: VELCADE®, ATC code: L01XX32
Drug: Doxorubicin
18mg/m2 i.v. (days 1 and 8)/ 28 day treatment cycle, max. 6 treatment cycles
Other Name: ADRIMEDAC®
Drug: Dexamethasone
40mg abs. p.o. (days 1,8,15,22) 1st treatment cycle, 20mg abs. p.o.(days 1,8,15,22) 2-6 treatment cycles
Other Name: FORTECORTIN®

Detailed Description:

A first cohort of three patients will be treated at the starting dose level of Vorinostat 100 mg/d, on day 1-4, 8-11, and 15-18 in combination with BDD.

The dose level of Vorinostat will be escalated in each new cohort:

if no dose limiting toxicity (DLT) has been observed in the previous dose level in 3 patient, the second cohort of 3 new patients will be treated with Vorinostat 200 mg/d and the third cohort will be given Vorinostat with 300 mg/d.

Bortezomib will be administered intravenously (i.v.) 1.3mg/m2 d1, 8, 15. Doxorubicin will be administered i.v. with a total dose of 18 mg/m2 per cycle (9 mg/m2, d1 and 8).

Dexamethasone will be administered per os (p.o.) with 40mg (first cycle) and 20mg (all other subsequent cycles) on d1, 8, 15, 22.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.
  • KPS ≥60%
  • Adequate BM function
  • Adequate hepatic and renal function (AST and ALT ≤2.5 times ULN, Bilirubin ≤1.5 times ULN, eGFR >20 ml/min)

Exclusion Criteria:

  • Patient has had prior treatment with Vorinostat or HDAC inhibitors
  • Patients with severe hepatic impairment or acute diffuse infiltrative pulmonary and pericardial disease
  • Patient has preexisting NCI CTC ≥grade 3 neuropathy
  • Patient with known CNS MM-involvement and/or MM-related/induced meningitis
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01394354

Locations
Germany
University Medical Center Freiburg Recruiting
Freiburg, Germany, 79106
Contact: Monika Engelhardt, MD    +49 761 270 32460    monika.engelhardt@uniklinik-freiburg.de   
Principal Investigator: Monika Engelhardt, MD         
Sponsors and Collaborators
University Hospital Freiburg
Merck Sharp & Dohme Corp.
Janssen-Cilag Ltd.
Investigators
Principal Investigator: Monika Engelhardt, MD University of Freiburg Medical School
  More Information

No publications provided

Responsible Party: Monika Engelhardt, Prof. Dr. med., University Hospital Freiburg
ClinicalTrials.gov Identifier: NCT01394354     History of Changes
Other Study ID Numbers: 00658, MK-0683-201
Study First Received: June 21, 2011
Last Updated: June 27, 2014
Health Authority: Germany: Bundesinstitut für Arzneimittel und Medizinprodukte, Klinische Studien, Kurt-Georg-Kiesinger-Allee 3,53175 Bonn

Keywords provided by University Hospital Freiburg:
Multiple Myeloma relapsed refractory

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Liposomal doxorubicin
Bortezomib
Vorinostat
Doxorubicin
BB 1101
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents

ClinicalTrials.gov processed this record on September 18, 2014