Back to resultsVorinostat in Combination With Bortezomib, Doxorubicin and Dexamethasone (VBDD) in Patients With Refractory or Relapsed Multiple Myeloma (MM) (VBDD)
Primary Purpose
Multiple Myeloma in Relapse
Status
Completed
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
Vorinostat
Bortezomib
Doxorubicin
Dexamethasone
Sponsored by
About this trial
This is an interventional treatment trial for Multiple Myeloma in Relapse focused on measuring Multiple Myeloma relapsed refractory
Eligibility 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
Sites / Locations
- University Medical Center Freiburg
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
1
Arm Description
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.
Outcomes
Primary Outcome Measures
Maximal Tolerated Dose (MTD)
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
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
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
Assessment with Quality of Life-Questionnaire SF-12
Duration of Response
Clinical assessment
Progression-free survival (PFS)
estimation by using Kaplan-Meier method
Overall survival (OS)
estimation by using Kaplan-Meier method
Full Information
NCT ID
NCT01394354
First Posted
June 21, 2011
Last Updated
April 5, 2016
Sponsor
University Hospital Freiburg
Collaborators
Merck Sharp & Dohme LLC, Janssen-Cilag Ltd.
1. Study Identification
Unique Protocol Identification Number
NCT01394354
Brief Title
Vorinostat in Combination With Bortezomib, Doxorubicin and Dexamethasone (VBDD) in Patients With Refractory or Relapsed Multiple Myeloma (MM)
Acronym
VBDD
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
Study Type
Interventional
2. Study Status
Record Verification Date
April 2016
Overall Recruitment Status
Completed
Study Start Date
August 2011 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
December 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital Freiburg
Collaborators
Merck Sharp & Dohme LLC, Janssen-Cilag Ltd.
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma in Relapse
Keywords
Multiple Myeloma relapsed refractory
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
34 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Vorinostat
Other Intervention Name(s)
ZOLINZA®, ATC code: L01XX
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Other Intervention Name(s)
VELCADE®, ATC code: L01XX32
Intervention Description
1.3mg/m2 (days 1,8,15)/28 day treatment cycle, i.v., for max. 6 treatment cycles
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
ADRIMEDAC®
Intervention Description
18mg/m2 i.v. (days 1 and 8)/ 28 day treatment cycle, max. 6 treatment cycles
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Other Intervention Name(s)
FORTECORTIN®
Intervention Description
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
Primary Outcome Measure Information:
Title
Maximal Tolerated Dose (MTD)
Description
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.
Time Frame
28 days (within first treatment cycle)
Secondary Outcome Measure Information:
Title
Response
Description
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.
Time Frame
up to 1 year after inclusion of the last patient
Title
Rates of Adverse Events (AE),Serious Adverse Events and AEs leading to permanent treatment discontinuation
Description
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.
Time Frame
9 months
Title
Quality of Life
Description
Assessment with Quality of Life-Questionnaire SF-12
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)
Title
Duration of Response
Description
Clinical assessment
Time Frame
up to one year after inclusion of the last patient
Title
Progression-free survival (PFS)
Description
estimation by using Kaplan-Meier method
Time Frame
up to 1 year after inclusion of the last patient
Title
Overall survival (OS)
Description
estimation by using Kaplan-Meier method
Time Frame
up to 1 year after inclusion of the last patient
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Monika Engelhardt, MD
Organizational Affiliation
University of Freiburg Medical School
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Medical Center Freiburg
City
Freiburg
ZIP/Postal Code
79106
Country
Germany
12. IPD Sharing Statement
Learn more about this trial
Vorinostat in Combination With Bortezomib, Doxorubicin and Dexamethasone (VBDD) in Patients With Refractory or Relapsed Multiple Myeloma (MM)
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