TEAM-Trial: Targeting Epigenetic Therapy Resistance in AML With Bortezomib

NCT04173585 | Completed Phase 2 DMC

• 1 other identifier: NCT-2017-0530
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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 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.

Conditions

Acute Myeloid Leukemia

Keywords

Acute Myeloid Leukemia; therapy resistance; refractory/relapsed; AML

Outcome Measures

Primary Outcomes (1)

• CR/CRi rate

  Primary endpoint is the CR/CRi rate (response rate), defined as the proportion of patients achieving a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) according to ELN 2017 criteria after B-GA treatment.

  two years

Study Arms (1)

Bortezomib-Gemtuzumab Ozogamicin Treatment

EXPERIMENTAL

one cycle of combined chemotherapy: * Bortezomib (1.3 mg/m2) sc on day 1 and 3. Dose will be given 3 hours prior to Cytarabine on day 1 and 3 * Cytarabine (1g/m² twice daily) iv over 3 hours on day 1, 2 and 3 Gemtuzumab Ozogamicin (3 mg/m²,up to a maximum of one 5 mg vial) iv over 2 hours on day 1 after first dose of Cytarabine and day 4 * Pegfilgrastim 6 mg sc on day 8 (optional)

Drug: Bortezomib; Drug: Gemtuzumab Ozogamicin

Interventions

Bortezomib DRUG

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.

Also known as: Velcade

Bortezomib-Gemtuzumab Ozogamicin Treatment

Gemtuzumab Ozogamicin DRUG

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.

Also known as: Mylotarg

Bortezomib-Gemtuzumab Ozogamicin Treatment

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with confirmed diagnosis of AML according to WHO-2016 \[27\] (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 (A) to first line chemotherapy or in first relapse (B), also after stem cell transplantation. FLT3-ITD status, cytogenetics (refractory and relapsed patients), in addition status of core-binding-factor as well as double mutant CEBPA in relapsed patients must be available.
• A) Refractory to induction therapy is defined as no CR, CRi (according to standard criteria) \[4\] after 2 intensive induction cycles of at least 7 days of cytarabine 100-200 mg/m² continuously or an equivalent regimen with cytarabine with total dose not less than 700 mg/m² per cycle and 3 days of an anthracycline/ anthraquinone (e.g. daunorubicin, idarubicin).
• B) Relapsed after first line therapy is defined as relapsed AML after CR or CRi (according to standard criteria) after at least one intensive induction and consolidation (including intensive chemotherapy and/or hematopoietic cell transplantation) therapy.
• ECOG performance status ≤ 2
• Discontinuation of prior AML treatment before the start of study treatment (except hydroxyurea or other treatment to control hyperleukocytosis) for at least 10 days for cytotoxic agents and 5 half-lives for non-cytotoxic/ investigational drug treatment preceding the first dose of trial medications
• Age ≥ 18 years
• Pregnancy and childbearing potential:
• Non-pregnant and non-nursing women of childbearing potential must have a negative serum or urine ß-HCG pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to registration ("Women of childbearing potential" is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months).
• Female patients of reproductive age must agree to avoid getting pregnant while on therapy.
• Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin highly effective methods of birth control during study and for at least 7 months after end of treatment.
• Men must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy and must agree to avoid to father a child during study and until 6 months after end of study/treatment.
• Willingness of patient to adhere to protocol specific requirements and capacity to give written informed consent
• Ability of patient to understand the character and individual consequences of clinical Trial
• Following receipt of verbal and written information about the study, the patient must provide signed informed consent before any study related activity is carried out

You may not qualify if:

• Acute promyelocytic leukemia (AML M3)
• Acute myeloid leukemia previously treated with gemtuzumab ozogamicin
• Hyperleukocytosis (leukocytes \> 30,000/μl) at the time of study entry. These patients should be treated with hydroxyurea and / or receive leukocytapheresis treatment according to routine practice and are only allowed to enter into the study when leukocyte counts of 30,000/μl or below are reached. If hydroxyurea is not sufficient to control hyperleukocytosis i.v. application of 100 mg cytarabine continuously over 24 hours may be discussed with the coordinating investigator or the scientific coordinator
• Known central nervous system manifestation of AML
• uncontrolled or significant cardiovascular disease, including any of the following:
• History of heart failure NYHA class 3 or 4
• Left ventricular ejection fraction (LVEF) ≤ 40% by echocardiogram
• History of uncontrolled angina pectoris or myocardial infarction within 12 months prior to screening
• History of second (Mobitz II) or third degree heart block or any cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
• Pregnant or nursing woman
• Chronically impaired renal function (creatinine clearance \< 30 ml / min)
• Inadequate liver function (ALT and AST ≥ 2 x ULN), total bilirubin ≥ 1.5 x ULN
• Known liver cirrhosis or history of veno-occlusive disease (VOD)
• HIV infection and/or active hepatitis B or C infection (active hepatitis B defined by HBs Ag positivity, active hepatitis C defined by positive virus load)
• Evidence or history of severe non-leukemia associated bleeding diathesis or coagulopathy

Sponsors & Collaborators

• University Hospital Heidelberg: lead
• National Center for Tumor Diseases, Heidelberg: collaborator

Study Sites (1)

University Hospital Heidelberg, Internal Medicine V

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Recurrence

Interventions

Bortezomib; Gemtuzumab

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Calicheamicins; Aminoglycosides; Glycosides; Carbohydrates; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Carsten Müller-Tidow, Prof., MD

  Medical Director of Internal Medicine V, University Hospital Heidelberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Scientific Coordinator

Model Details: Simon's Optimal Two-Stage Design: The Matched Threshold Crossing (MTC) Design

Study Record Dates

• First Submitted: November 20, 2019
• First Posted: November 22, 2019
• Study Start: October 22, 2019
• Primary Completion: February 28, 2023
• Study Completion: March 24, 2023
• Last Updated: March 27, 2023

Record last verified: 2023-03

Locations

DE (1)