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

Multiple Myeloma in Relapse Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01394354
• Other study ID #: 00658, MK-0683-201
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: June 21, 2011
• Last updated: April 5, 2016
• Start date: August 2011
• Est. completion date: December 2015

Study information

• Verified date: April 2016
• Source: University Hospital Freiburg
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Bundesinstitut für Arzneimittel und Medizinprodukte, Klinische Studien, Kurt-Georg-Kiesinger-Allee 3,53175 Bonn
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Multiple Myeloma in Relapse
• Neoplasms, Plasma Cell

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.
• Bortezomib
1.3mg/m2 (days 1,8,15)/28 day treatment cycle, i.v., for max. 6 treatment cycles
• Doxorubicin
18mg/m2 i.v. (days 1 and 8)/ 28 day treatment cycle, max. 6 treatment cycles
• 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

Locations

Country	Name	City	State
Germany	University Medical Center Freiburg	Freiburg

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital Freiburg	Janssen-Cilag Ltd., Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	28 days (within first treatment cycle)	Yes
Secondary	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.	up to 1 year after inclusion of the last patient	Yes
Secondary	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.	9 months	Yes
Secondary	Quality of Life	Assessment with Quality of Life-Questionnaire SF-12	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)	No
Secondary	Duration of Response	Clinical assessment	up to one year after inclusion of the last patient	Yes
Secondary	Progression-free survival (PFS)	estimation by using Kaplan-Meier method	up to 1 year after inclusion of the last patient	Yes
Secondary	Overall survival (OS)	estimation by using Kaplan-Meier method	up to 1 year after inclusion of the last patient	Yes