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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Multiple Myeloma in Relapse

Intervention / Treatment
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* Drug: Vorinostat
* Drug: Bortezomib
* Drug: Doxorubicin
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>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<br>* 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.<br>* Other names: ZOLINZA®, ATC code: L01XX;Drug: Bortezomib<br>* 1.3mg/m2 (days 1,8,15)/28 day treatment cycle, i.v., for max. 6 treatment cycles<br>* Other names: VELCADE®, ATC code: L01XX32;Drug: Doxorubicin<br>* 18mg/m2 i.v. (days 1 and 8)/ 28 day treatment cycle, max. 6 treatment cycles<br>* Other names: ADRIMEDAC®;Drug: Dexamethasone<br>* 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<br>* Other names: FORTECORTIN®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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) | 
| Duration of Response | Clinical assessment | up to one year after inclusion of the last patient | 
| Progression-free survival (PFS) | estimation by using Kaplan-Meier method | up to 1 year after inclusion of the last patient | 
| Overall survival (OS) | estimation by using Kaplan-Meier method | up to 1 year after inclusion of the last patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma relapsed refractory