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

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

Overview[ - collapse ][ - ]

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	Multiple Myeloma in Relapse
Intervention	Drug: Vorinostat Drug: Bortezomib Drug: Doxorubicin Drug: Dexamethasone
Phase	Phase 1/Phase 2
Sponsor	University Hospital Freiburg
Responsible Party	University Hospital Freiburg
ClinicalTrials.gov Identifier	NCT01394354
First Received	June 21, 2011
Last Updated	September 12, 2011
Last verified	September 2011

Tracking Information[ + expand ][ + ]

First Received Date	June 21, 2011
Last Updated Date	September 12, 2011
Start Date	August 2011
Estimated Primary Completion Date	September 2014
Current 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.
Current 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

Descriptive Information[ + expand ][ + ]

Brief Title	Vorinostat in Combination With Bortezomib, Doxorubicin and Dexamethasone (VBDD) in Patients With Refractory or Relapsed Multiple Myeloma (MM)
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
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.
Study Type	Interventional
Study Phase	Phase 1/Phase 2
Study Design	Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Condition	Multiple Myeloma in Relapse
Intervention	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 Names: ZOLINZA®, ATC code: L01XXDrug: Bortezomib 1.3mg/m2 (days 1,8,15)/28 day treatment cycle, i.v., for max. 6 treatment cycles Other Names: VELCADE®, ATC code: L01XX32Drug: Doxorubicin 18mg/m2 i.v. (days 1 and 8)/ 28 day treatment cycle, max. 6 treatment cycles Other Names: 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 Names: FORTECORTIN®
Study Arm (s)	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.

Recruitment Information[ + expand ][ + ]

Recruitment Status	Recruiting
Estimated Enrollment	30
Estimated Completion Date	September 2014
Estimated Primary Completion Date	August 2013
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
Gender	Both
Ages	18 Years
Accepts Healthy Volunteers	No
Contacts	Not Provided
Location Countries	Germany

Administrative Information[ + expand ][ + ]

NCT Number	NCT01394354
Other Study ID Numbers	00658, MK-0683-201
Has Data Monitoring Committee	No
Information Provided By	University Hospital Freiburg
Study Sponsor	University Hospital Freiburg
Collaborators	Merck Sharp & Dohme Corp. Janssen-Cilag Ltd.
Investigators	Principal Investigator: Monika Engelhardt, MD University of Freiburg Medical School
Verification Date	September 2011

Locations[ + expand ][ + ]

University Medical Center Freiburg	Freiburg, Germany, 79106 Contact: Monika Engelhardt, MD \| +49 761 270 32460 \| monika.engelhardt@uniklinik-freiburg.de Principal Investigator: Monika Engelhardt, MD Recruiting