TEAM-Trial: Targeting Epigenetic Therapy Resistance in AML With Bortezomib
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 2

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
      refractory/relapsed 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 mg/m² 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.
    

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 refractory/relapsed 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 relapsed/refractory AML patients. This epigenetic
      mediated resistance can be successfully overcome in in vitro models by proteasome inhibition.
      Currently, relapsed and refractory r/r-AML still carries a dismal prognosis. In this
      multicentre, phase II trial the investigators will analyze efficacy of a novel therapy
      regimen for r/r-AML.

      As detailed above, combination-chemotherapy including GO and HiDAC based chemotherapy is an
      effective regimen in r/r-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 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. 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 r/r-AML given high-dose
      cytarabine (2 g/m²/day) 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.
    

Intervention name(s): Bortezomib; Gemtuzumab Ozogamicin
Intervention type(s): Drug; Drug
Intervention description(s): Bortezomib is a small molecule dipeptide binding the catalytic site of the 26 S proteasome. It acts as a potent, reversible, and specific inhibitor of proteasomes and thus impairs the degradation of ubiquitinated proteins. It has demonstrated anti-neoplastic activity in myeloma and lymphoma. It is approved and widely used in multiple myeloma both for first line treatment and relapsed patients.; Gemtuzumab Ozogamicin is a monoclonal antibody directed against the myeloid surface antigen CD33. The antibody is linked to calicheamicin which serves as cytotoxic agent. For years, gemtuzumab ozogamicin has been tested in clinical AML trials. Though withdrawn from the US market in 2010, FDA approval was granted in September 2018, EU approval in April 2018 based on encouraging results from recent clinical trials using enhanced dosing schedules.
Other intervention name(s): Velcade; Mylotarg
Intervention MeSH terms: Bortezomib; Gemtuzumab
Intervention model: Single Group Assignment
Intervention model description: Simon's Optimal Two-Stage Design: The Matched Threshold Crossing (MTC) Design
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute Myeloid Leukemia; therapy resistance; refractory/relapsed; AML