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

Phase 1

Terminated

• Conditions: Relapsed AML; Refractory AML; Acute Myeloid Leukemia
• Interventions: Drug: GEM333

• Registration Number: NCT03516760
• Lead Sponsor: AvenCell Europe GmbH

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-04-06
• Study Start: 2018-04-11
• Study First Submitted QC: 2018-05-03
• Study First Posted: 2018-05-04
• Primary Completion: 2022-06-14
• Study Completion: 2022-06-14
• Status Verified: 2022-09
• Last Update Submitted: 2022-09-28
• Last Update Posted: 2022-09-29

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 36

Inclusion Criteria

1. Male or female patients, ≥ 18 years of age

2. 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

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

4. Life expectancy of at least 2 months

5. Adequate renal and hepatic laboratory assessments:

6. Adequate cardiac function, i.e. left ventricular ejection fraction (LVEF) of ≥ 45% as assessed by transthoracal two-dimensional echocardiography

7. 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.

8. Able to give written informed consent

9. Weight ≥ 45 kg

Exclusion Criteria

1. Acute promyelocytic leukemia (t15;17)
2. Manifestation of AML in central nervous system
3. Leukocytosis > 10 Gpt/L
4. 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
5. Patients undergoing renal dialysis
6. Pulmonary disease with clinical relevant hypoxia (need for continuous oxygen inhalation)
7. Active central nervous diseases (e.g. parkinson, multiple sclerosis, epilepsy) and stroke within last 6 months
8. Active infectious disease considered by investigator to be incompatible with protocol
9. Allogeneic stem cell transplantation within last three months or GvHD requiring immune-suppressive therapy
10. Major surgery within 28 days prior to start of study medication
11. Other malignancy requiring active therapy but adjuvant endocrine therapy is allowed
12. Checkpoint inhibitors und CD33 targeting agents within 8 weeks prior to start of trial medication
13. Autoimmune diseases requiring systemic steroids or other systemic immunosuppressants
14. 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
15. Pregnant or breastfeeding women
16. Psychologic disorders, drug and/or significant active alcohol abuse
17. Known history of human immunodeficiency virus (HIV) or active/chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)
18. Known hypersensitivity to GEM333 excipients
19. Evidence suggesting that the patient is not likely to follow the study protocol (e.g. lacking compliance)
20. Incapability of understanding purpose and possible consequences of the trial
21. Patients who should not be included according to the opinion of the investigator

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
GEM333	GEM333	application of GEM333, a CD33 targeted bispecific antibody engaging T-cells

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (7)

Klinikum rechts der Isar; 🇩🇪 München, Bayern, Germany

Universitätsklinikum Würzburg; 🇩🇪 Würzburg, Bayern, Germany

Universitätsklinikum Dresden; 🇩🇪 Dresden, Sachsen, Germany

Universitätsklinikum Frankfurt; 🇩🇪 Frankfurt am Main, Hessen, Germany

Universitätsklinikum Marburg; 🇩🇪 Marburg, Hessen, Germany

Charité Universitätsmedizin; 🇩🇪 Berlin, Germany

Universitätsmedizin Mannheim; 🇩🇪 Mannheim, Baden-Württemberg, Germany