Clinical trial NCT03516760: Dose-escalating Phase I Trial With GEM333 in Patients With Acute Myeloid Leukemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Relapsed AML
Refractory AML
Lead sponsor: AvenCell Europe GmbH
Sponsor class: INDUSTRY
Collaborators: name: GCP-Service International Ltd. & Co. KG
First posted: 2018-05-04
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Dose escalation scheme; Single patient cohorts on the first three dose levels, 3+3 afterwards.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Maximum tolerated dose (MTD)
timeFrame: End of Treatment (EOT) +8 days resp. +28 days (DLT period)
measure: Incidence of dose limiting toxicity (DLT)
timeFrame: End of Treatment (EOT) +8 days resp. +28 days
measure: Incidence and intensity of adverse events graded according to CTCAE V4.03
timeFrame: End of Treatment (EOT) +8 days resp. +28 days
Secondary outcomes:
measure: Recommended phase 2 dose
timeFrame: 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).
measure: Complete remission (CR)
timeFrame: until two years after start of study medication
measure: Composite complete remission (CRc) rate
timeFrame: until two years after start of study medication
measure: Partial Remission (PR)
timeFrame: until two years after start of study medication
measure: Disease stabilization (DS)
timeFrame: until two years after start of study medication
measure: Best response rate
timeFrame: until two years after start of study medication
measure: Duration of CRc
timeFrame: until two years after start of study medication
measure: Duration of PR
timeFrame: until two years after start of study medication
measure: Progression free survival (PFS)
timeFrame: until two years after start of study medication
measure: Overall survival
timeFrame: until two years after start of study medication
Other outcomes:
Locations:
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim
state: Baden-Württemberg
city: München
country: Germany
facility: Klinikum rechts der Isar
state: Bayern
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
state: Bayern
city: Frankfurt am Main
country: Germany
facility: Universitätsklinikum Frankfurt
state: Hessen
city: Marburg
country: Germany
facility: Universitätsklinikum Marburg
state: Hessen
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden
state: Sachsen
city: Berlin
country: Germany
facility: Charité Universitätsmedizin
Study officials:
affiliation: Universitätsklinikum Carl Gustav Carus Dresden
name: Martin Wermke, MD
role: PRINCIPAL_INVESTIGATOR
References: