Ignite Creation Date:
2024-05-06 @ 1:57 PM
Last Modification Date:
2024-10-26 @ 1:22 PM
Study NCT ID:
NCT04173585
Status:
COMPLETED
Last Update Posted:
2023-03-27
First Post:
2019-11-20
Brief Title:
TEAM-Trial Targeting Epigenetic Therapy Resistance in AML With Bortezomib
Sponsor:
University Hospital Heidelberg
Organization:
University Hospital Heidelberg
Study Overview
Official Title:
TEAM-Trial Targeting Epigenetic Therapy Resistance in AML With Bortezomib A Multi-centre Matched Threshold Crossing Phase II Approach
Status:
COMPLETED
Status Verified Date:
2023-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
TEAM
Brief Summary:
The long-term outcome of patients with acute myeloid leukemia AML remains poor with less than 30 of patients achieving long lasting remission or cure This poor outcome is largely due to refractoriness to induction chemotherapy as well as relapses during and after completion of intensive induction and consolidation therapy In patients with refractoryrelapsed AML hematopoietic cell transplantation allo-HCT is currently the only treatment option offering a prospect of cure but outcome is heavy influenced by the remission status before allo-HCT Therefore patients are typically treated with salvage regimens based on high dose cytarabine HiDAC combined with mitoxantrone fludarabine or idarubicin Nevertheless the remission rates remain poor and currently there is no accepted standard salvage regimen Recent studies indicate that combination chemotherapy including HiDAC and gemtuzumab ozogamicin GO at a dose of 3 mgm² leads to improved response rates in refractory AML
Proteasome inhibition with bortezomib appears to be a promising treatment strategy to restore chemo-sensitivity via EZH2 stabilisation
This study aims at improving response rates in refractory relapsed AML by combining high dose cytarabine gemtuzumab ozogamicin GA and bortezomib B
During this phase II study efficacy of B-GA is assessed in comparison to matched historical controls using the Matched Threshold Crossing MTC-approach If results are promising a subsequent randomized phase III study is intended to assess the efficacy of GA with or without bortezomib
Proteasome inhibition with bortezomib appears to be a promising treatment strategy to restore chemo-sensitivity via EZH2 stabilisation
This study aims at improving response rates in refractory relapsed AML by combining high dose cytarabine gemtuzumab ozogamicin GA and bortezomib B
During this phase II study efficacy of B-GA is assessed in comparison to matched historical controls using the Matched Threshold Crossing MTC-approach If results are promising a subsequent randomized phase III study is intended to assess the efficacy of GA with or without bortezomib
Detailed Description:
Acute Myeloid Leukemia AML is a clonal malignant disorder which is characterized by the expansion of leukemic blasts in the bone marrow and the peripheral blood which goes along with a suppression of normal hematopoiesis including granulopoiesis erythropoiesis and thrombocytopoiesis The prognosis is largely determined by cytogenetic and molecular risk factors age performance status and antecedent Myelodysplastic Syndrome MDS
With the exception of old and frail patients most AML patients are eligible for intensive chemotherapy which is given in curative intent consisting of induction and consolidation therapy However despite intensive therapy the long-term outcome of AML patients remains poor with less than 30 of patients achieving long lasting remission and even cure This poor outcome is largely due to refractoriness to induction chemotherapy as well as relapses during and after completion of intensive induction and consolidation therapy Regarding refractoriness about 20-30 of AML patients under the age of 60 years and about 50 of older patients fail to attain complete remission CR following cytarabine plus anthracycline based standard induction therapy Regarding relapses even patients having achieved complete remission are at a high risk of relapse particularly within the first two years after completion of chemotherapy
In patients with blast persistence after induction therapy or relapse allogeneic hematopoietic cell transplantation allo-HCT is currently the only treatment strategy to offer the prospect of cure Outcome of allo-HCT is heavily influenced by the remission state before allo-HCT With the aim to induce a complete remission CR before allo-HCT salvage chemotherapy regimens are administered in refractoryrelapsed patients Typically these salvage regimens are based on high dose cytarabine HiDAC which is frequently combined with either mitoxantrone HAM regimen or fludarabine plus idarubicin idaFLA regimen Currently there is no commonly accepted standard salvage regime but a large individual patient data meta-analysis and single arm phase-II studies suggest that combination chemotherapy including HiDAC and gemtuzumab ozogamicin an antibody drug conjugate are very effective Since patients with refractory or relapsed AML are candidates for allo-HCT the main purpose of the salvage regimen is to bridge patients to allo-HCT with induction of a CR before allo-HCT Therapy resistance in cancer is still poorly understood Beyond genetic aberrations epigenetic mechanisms are important components of resistance to cancer therapy Recently the investigators discovered an epigenetic therapy resistance mechanism in AML Figure 1 This mechanism might be relevant in up to 50 of relapsedrefractory AML patients This epigenetic mediated resistance can be successfully overcome in in vitro models by proteasome inhibition Currently relapsed and refractory rr-AML still carries a dismal prognosis In this multicentre phase II trial the investigators will analyze efficacy of a novel therapy regimen for rr-AML
As detailed above combination-chemotherapy including GO and HiDAC based chemotherapy is an effective regimen in rr-AML
Proteasome inhibitors can restore EZH2 protein levels in vitro and in vivo The restoration of EZH2 significantly improved efficacy of anti-leukemic therapy Based on the data mentioned above 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 the investigators believe that they can substantially improve treatment results in rr-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 There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis interstitial pneumonia lung infiltration and Acute Respiratory Distress Syndrome ARDS in patients receiving bortezomib In particular 2 patients with rr-AML given high-dose cytarabine 2 gm²day by continuous infusion in combination with daunorubicin and bortezomib died of ARDS early in the course of therapy However in several trials evaluating the combination of bortezomib with standard and high-dose cytarabine in AML patients no toxicity signal was detected especially with respect to ARDS
Taken together the rationale for this trial is based on the high unmet clinical need and strong in vitro evidence
With the exception of old and frail patients most AML patients are eligible for intensive chemotherapy which is given in curative intent consisting of induction and consolidation therapy However despite intensive therapy the long-term outcome of AML patients remains poor with less than 30 of patients achieving long lasting remission and even cure This poor outcome is largely due to refractoriness to induction chemotherapy as well as relapses during and after completion of intensive induction and consolidation therapy Regarding refractoriness about 20-30 of AML patients under the age of 60 years and about 50 of older patients fail to attain complete remission CR following cytarabine plus anthracycline based standard induction therapy Regarding relapses even patients having achieved complete remission are at a high risk of relapse particularly within the first two years after completion of chemotherapy
In patients with blast persistence after induction therapy or relapse allogeneic hematopoietic cell transplantation allo-HCT is currently the only treatment strategy to offer the prospect of cure Outcome of allo-HCT is heavily influenced by the remission state before allo-HCT With the aim to induce a complete remission CR before allo-HCT salvage chemotherapy regimens are administered in refractoryrelapsed patients Typically these salvage regimens are based on high dose cytarabine HiDAC which is frequently combined with either mitoxantrone HAM regimen or fludarabine plus idarubicin idaFLA regimen Currently there is no commonly accepted standard salvage regime but a large individual patient data meta-analysis and single arm phase-II studies suggest that combination chemotherapy including HiDAC and gemtuzumab ozogamicin an antibody drug conjugate are very effective Since patients with refractory or relapsed AML are candidates for allo-HCT the main purpose of the salvage regimen is to bridge patients to allo-HCT with induction of a CR before allo-HCT Therapy resistance in cancer is still poorly understood Beyond genetic aberrations epigenetic mechanisms are important components of resistance to cancer therapy Recently the investigators discovered an epigenetic therapy resistance mechanism in AML Figure 1 This mechanism might be relevant in up to 50 of relapsedrefractory AML patients This epigenetic mediated resistance can be successfully overcome in in vitro models by proteasome inhibition Currently relapsed and refractory rr-AML still carries a dismal prognosis In this multicentre phase II trial the investigators will analyze efficacy of a novel therapy regimen for rr-AML
As detailed above combination-chemotherapy including GO and HiDAC based chemotherapy is an effective regimen in rr-AML
Proteasome inhibitors can restore EZH2 protein levels in vitro and in vivo The restoration of EZH2 significantly improved efficacy of anti-leukemic therapy Based on the data mentioned above 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 the investigators believe that they can substantially improve treatment results in rr-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 There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis interstitial pneumonia lung infiltration and Acute Respiratory Distress Syndrome ARDS in patients receiving bortezomib In particular 2 patients with rr-AML given high-dose cytarabine 2 gm²day by continuous infusion in combination with daunorubicin and bortezomib died of ARDS early in the course of therapy However in several trials evaluating the combination of bortezomib with standard and high-dose cytarabine in AML patients no toxicity signal was detected especially with respect to ARDS
Taken together the rationale for this trial is based on the high unmet clinical need and strong in vitro evidence
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None