Dose-escalating Phase I Trial With GEM333 in Patients With Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This dose-escalating phase I trial assesses for the first time the safety, the side effects and the harmlessness, as well as the therapeutical benefit of the new study drug GEM333 in patients with acute myeloid leukemia (AML). This AML was relapsed after previous therapy or was refractory to the standard therapy.

Official Title
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A Multicenter, Open-label, Dose-escalating, Phase I Trial With GEM333, a CD33 Targeted Bispecific Antibody Engaging T-cells, in Relapsed or Refractory Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia, Relapsed AML, Refractory AML

Intervention / Treatment
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* Drug: GEM333


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients, ≥ 18 years of age Documented definitive diagnosis of CD33 positive AML (according to standard of care testing) in 2a. Patients having received standard induction chemotherapy: either refractory to standard induction treatment, or is relapsed within 6 months after achieving 1st CR, or relapsed later than 6 months after 1st CR and refractory to standard salvage regimen, or relapse after ≥ 2nd CR and not eligible for curative treatment (i.e. allogeneic stem cell transplantation) 2b. Patients not eligible for standard induction chemotherapy: either refractory or progressive after at least 1 cycle of demethylating agents Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Life expectancy of at least 2 months Adequate renal and hepatic laboratory assessments: Adequate cardiac function, i.e. left ventricular ejection fraction (LVEF) of ≥ 45% as assessed by transthoracal two-dimensional echocardiography A female of childbearing potential may be enrolled providing she has a negative pregnancy test at screening visit and is routinely using a highly effective method of birth control (pearl index of ≤ 1 required) resulting in a low failure rate (e.g. hormonal contraception, intrauterine device, total sexual abstinence or sterilization) until 3 months from the last study drug administration. Male patients must also practice a highly effective method of birth control. Able to give written informed consent Weight ≥ 45 kg Exclusion Criteria: Acute promyelocytic leukemia (t15;17) Manifestation of AML in central nervous system Leukocytosis > 10 Gpt/L Cardiac disease: i.e. heart failure NYHA III or IV; unstable coronary artery disease (Myocardial Infarction more than 6 months prior to study entry is permitted); serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy Patients undergoing renal dialysis Pulmonary disease with clinical relevant hypoxia (need for continuous oxygen inhalation) Active central nervous diseases (e.g. parkinson, multiple sclerosis, epilepsy) and stroke within last 6 months Active infectious disease considered by investigator to be incompatible with protocol Allogeneic stem cell transplantation within last three months or GvHD requiring immune-suppressive therapy Major surgery within 28 days prior to start of study medication Other malignancy requiring active therapy but adjuvant endocrine therapy is allowed Checkpoint inhibitors und CD33 targeting agents within 8 weeks prior to start of trial medication Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants Treatment with any investigational drug substance or experimental therapy within 4 weeks prior to start of trial medication or 5 half lives of the substance prior to start of trial medication Pregnant or breastfeeding women Psychologic disorders, drug and/or significant active alcohol abuse Known history of human immunodeficiency virus (HIV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) Known hypersensitivity to GEM333 excipients Evidence suggesting that the patient is not likely to follow the study protocol (e.g. lacking compliance) Incapability of understanding purpose and possible consequences of the trial Patients who should not be included according to the opinion of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation scheme; Single patient cohorts on the first three dose levels, 3+3 afterwards.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GEM333<br>application of GEM333, a CD33 targeted bispecific antibody engaging T-cells | Drug: GEM333<br>* infusion of GEM333; administered intravenously and continuously over 10 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | MTD is the previous dose level of the cohort where a DLT is observed in at least wo subjects. | End of Treatment (EOT) +8 days resp. +28 days (DLT period) | 
| Incidence of dose limiting toxicity (DLT) | Dose Limiting Toxicity is defined as any event at least possibly related to IMP (complete definition provided protocol) | End of Treatment (EOT) +8 days resp. +28 days | 
| Incidence and intensity of adverse events graded according to CTCAE V4.03 |  | End of Treatment (EOT) +8 days resp. +28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase 2 dose | The RP2D will be determined based on MTD, all available efficacy data, and all available safety data, including information derived from additional treatment cycles. | From start of treatment until up to +28 days after last treatment cycle (1 initial cycle + max. 2 additional cycles per patient). Each cycle consists of 10 days treatment plus DLT evaluation period (8 resp. 28 days, depending on blast clearance). | 
| Complete remission (CR) | bone marrow blasts < 5%, absence of extramedullary disease, absolute neutrophil count > 1 Gpt/L and platelet count > 100 Gpt/L | until two years after start of study medication | 
| Composite complete remission (CRc) rate | Rate at any time point, defined as the proportion of patients having either CR or CRi | until two years after start of study medication | 
| Partial Remission (PR) | All hematological criteria for CR with bone marrow blasts 5-25% and decrease of pre-treatment bone marrow blast percentage by at least 50 %. | until two years after start of study medication | 
| Disease stabilization (DS) | Reduction of blast percentage by 25% compared to baseline without normalization of peripheral blood counts to levels not qualifying for PR or CR | until two years after start of study medication | 
| Best response rate | Defined as the best observed response at any time point during observational period. | until two years after start of study medication | 
| Duration of CRc | Defined as the number of days between the date of CR/CRi achievement and the date of the last assessment confirming CR/CRi | until two years after start of study medication | 
| Duration of PR | Defined as the number of days between the date of PR achievement and the date of the last assessment confirming PR. | until two years after start of study medication | 
| Progression free survival (PFS) | Is defined as the time from first treatment with GEM333 until disease progression or death from any cause | until two years after start of study medication | 
| Overall survival | Defined as the number of days between the first study drug administration and death from any cause | until two years after start of study medication |