Patients with confirmed diagnosis of Acute Myeloid Leukemia (AML)according to WHO-2016 classification (except acute promyelocytic leukemia) either de novo AML, AML after preceding myelodysplastic or myeloproliferative syndrome (MDS/MPD), and therapy related AML (t-AML) after previous cytotoxic therapy or radiation are eligible either refractory to first line chemotherapy or in first relapse, also after stem cell transplantation.
Conditions
Interventions
Trade Name: VELCADE
Product Name: VELCADE
Product Code: 63020-0049
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: BORTEZOMIB
CAS Number: 179324-69-7
Concentration unit: mg
Sponsors
Ruprecht-Karls-University Heidelberg Medical Faculty, University Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: See protocol chapter 5.3 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 35 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 15
Exclusion criteria
Exclusion criteria: See protocol chapter 5.4
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Relapsed and refractory r/r-AML still carries a dismal prognosis. In this multicentre, phase II trial we will analyze efficacy of a novel therapy regimen for r/r-AML by combining high dose cytarabine, gemtuzumab ozogamicin (GA) and bortezomib (B). Recent studies indicate that combination chemotherapy including high dose cytarabine (HiDAC) and gemtuzumab ozogamicin (GO), an antibody drug conjugate , at a dose of 3 mg/m² leads to improved response rates in refractory AML. ;Primary end point(s): Primary Endpoint: to assess efficacy (rates of CR/CRi) of B-GA according the ELN 2017 criteria in comparison to matched controls within the matched threshold crossing approach ;Secondary Objective: Therapy resistance in cancer is still poorly understood. Recently, we discovered an epigenetic therapy resistance mechanism in AML (Göllner et al, 2017). This mechanism might be relevant in up to 50% of relapsed/refractory AML patients. This epigenetic mediated resistance can be successfully overcome in in vitro models by proteasome inhibition. Proteasome inhibition with bortezomib appears to be a promising treatment strategy to restore chemo-sensitivity via EZH2 stabilisation. Based on this data we combine the treatment efficacy of GO plus cytarabine based chemotherapy with the proteasome inhibitor bortezomib in the B-GA regimen. With such an approach we believe that we can substantially improve treatment results in r/r-AML. Part of the study is a pre-specified biomarker analysis for EZH2 restoration after bortezomib exposure in vitro and in vivo. Accordingly, we will be able to determine whether EZH2 restoration after bortezomib exposure is associated with response and outcome.;Timepoint(s) of evaluation of this end point: Bone marrow aspiration will be performed at at baseline and for disease assessment after salvage therapy between day 22 and 56 at the time of peripheral blood cell regeneration after the chemotherapy induced nadir or at the time of clear signs | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Endpoint: Key secondary endpoint: safety and feasibility Other secondary endpoints: • to assess response in dependence of EZH2 protein levels • to assess EFS, RFS and OS • to assess MRD by flow cytometry • to assess QoL ;Timepoint(s) of evaluation of this end point: The key secondary endpoint safety will be assessed after 10, 22 and 35 patients based on SAE reporting whereby pulmonary events, prolonged thrombocytopenia and hepatotoxicity are of special interest. | — |
Countries
Germany
Contacts
Public ContactClinical Trials Office
University Hospital Heidelberg, Internal Medicine V: Hematology, Oncology and Rheumatology
Outcome results
None listed