Multiple Myeloma in Relapse
Conditions
Keywords
Multiple Myeloma relapsed refractory
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.
Interventions
DRUGVorinostat
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.
DRUGBortezomib
1.3mg/m2 (days 1,8,15)/28 day treatment cycle, i.v., for max. 6 treatment cycles
DRUGDoxorubicin
18mg/m2 i.v. (days 1 and 8)/ 28 day treatment cycle, max. 6 treatment cycles
DRUGDexamethasone
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
Sponsors
Merck Sharp & Dohme LLC
Janssen-Cilag Ltd.
University Hospital Freiburg
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Tolerated Dose (MTD) | 28 days (within first treatment cycle) | 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
| Measure | Time frame | Description |
|---|---|---|
| Rates of Adverse Events (AE),Serious Adverse Events and AEs leading to permanent treatment discontinuation | 9 months | 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 | 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) | Assessment with Quality of Life-Questionnaire SF-12 |
| Response | up to 1 year after inclusion of the last patient | 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. |
| Progression-free survival (PFS) | up to 1 year after inclusion of the last patient | estimation by using Kaplan-Meier method |
| Overall survival (OS) | up to 1 year after inclusion of the last patient | estimation by using Kaplan-Meier method |
| Duration of Response | up to one year after inclusion of the last patient | Clinical assessment |
Countries
Germany
Outcome results
None listed