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First-in-Human Dose Escalation Study of AFM28 in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Primary Purpose

Acute Myeloid Leukemia

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
AFM28
Sponsored by
Affimed GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: 1. Subjects with a confirmed diagnosis of AML as defined by 2016 WHO Classification and determined by pathology review at the study site. Subjects with acute promyelocytic leukemia are excluded. 2. Subjects must have CD123-positive AML confirmed on bone marrow or peripheral blood at Screening (assessed locally without any cut-off level). 3. Subjects with AML who are in the first, second, or third relapse OR who are at least primary refractory and received at most 3 regimes of previous standard anti-leukemia therapy. 4. Primary refractory is defined as ≥ 5% blasts in bone marrow following 2 cycles of anthracycline and cytarabine based induction (such as 3+7 or similar), or one cycle of purine analogue containing induction, or after ≥ 3 cycles hypomethylating agent ± or low dose cytarabine ± B-Cell lymphoma 2 based induction regimen, or ≥ 4 cycles of hypomethylating agent based therapy. 5. Subjects with prior autologous and allogeneic bone marrow transplant are eligible. Subjects with an allogeneic transplant must meet the following conditions: The transplant must have been performed > 3 months before the date of dosing on this study, the subject must not have active graft versus host disease, must be off all graft versus host disease medications at least > 28 days prior to date of dosing of study drug (for example, calcineurin inhibitors, ≥ 10 mg/day prednisone or other steroid equivalent, or other immunosuppressive agents). Exclusion Criteria: 1. Diagnosis of BCR-ABL-positive leukemia, acute promyelocytic leukemia, or juvenile myelomonocytic leukemia. 2. Known hypersensitivity/allergic reaction ≥ grade 3 to monoclonal antibodies or any components used in the AFM28 drug product preparation, any history of anaphylaxis or uncontrolled asthma. Prior CD123 targeting therapies should be allowed after discussion with and at the discretion of the Sponsor. 3. Received any anticancer therapy or investigational treatment for AML within 14 days of the first dose of study drug and within 28 days for biological agents including but not limited to monoclonal antibodies, cellular therapies, bispecific antibodies, checkpoint antibodies and others. Must have recovered to grade ≤ 1 from any grade 2 to 4 toxicity from previous treatment, except alopecia. 4. History of any other systemic malignancy, unless previously treated with curative intent and the subject has been disease free for 2 years or longer. Examples for acceptable previous malignancies include completely removed in situ cervical intra-epithelial neoplasia, non-melanoma skin cancer, ductal carcinoma in situ, early-stage prostate cancer that has been adequately treated. Subjects who meet the above criteria and are on maintenance therapy for the prior malignancy may be eligible after discussion and approval from the medical monitor. 5. The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment. 6. Known clinically active or suspected central nervous system (CNS) leukemia. If suspected, CNS leukemia should be ruled out with relevant imaging and/or examination of cerebrospinal fluid. Subjects with known prior CNS leukemia should have had at least two consecutive negative Lumbar Punctures for CNS leukemia and no clinical signs.

Sites / Locations

  • Institut Universitaire du Cancer Toulouse - Oncopole
  • Institut Català d'Oncologia-Hospital Duran i ReynalsRecruiting
  • Hospital Universitario 12 de Octubre
  • Hospital Universitari i Politècnic La FeRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment of escalating doses of AFM28

Arm Description

AFM28 first in human starting dose will be 25 mg i.v.

Outcomes

Primary Outcome Measures

The Incidence of dose limiting toxicities
The incidence of dose limiting toxicities during dose limiting toxicities observation period considering the totality of treatment-emergent adverse events is evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events, v5.0 the American Society of Transplantation and Cellular Therapy Cytokine Release Syndrome grading system for Cytokine Release Syndrome the Cairo-Bishop Tumor Lysing Syndrom (TLS) grading system for TLS

Secondary Outcome Measures

Incidence and severity of Treatment Emergent Adverse Events
Incidence and severity of Treatment Emergent Adverse Events
Incidence and severity of Serious Adverse Events
Incidence and severity of Serious Adverse Events
Incidence of subjects developing anti-drug antibodies
Incidence of anti-drug antibodies during treatment with AFM28 (by measurement of anti-drug antibodies before and throughout treatment with AFM28)
Area under the concentration-time curve
Area under the concentration-time curve over the dose interval
Cmax
Maximum observed plasma concentration
Tmax
Time to reach maximum observed plasma concentration
Ctrough
Concentration measured immediately prior to the fourth dose
Complete Response
Complete response (Disease assessment in accordance with the International Working Group (IWG) criteria for AML and the European Leukemia Network (ELN) 2017 classification criteria)
Complete Response hematological
Complete Response with partial hematologic recovery (Disease assessment in accordance with the IWG criteria for AML and the ELN 2017 classification criteria)
Complete Response composite rate
Composite complete response rate (Disease assessment in accordance with the IWG criteria for AML and the ELN 2017 classification criteria)
Complete Response + Complete Response hematological rate
Complete Response plus Complete Response with partial hematologic recovery rate (Disease assessment in accordance with the IWG criteria for AML and the ELN 2017 classification criteria)
Overall Response Rate
Overall response rate (Disease assessment in accordance with the IWG criteria for AML and the ELN 2017 classification criteria)
Disease Control Rate
Disease control rate (Disease assessment in accordance with the IWG criteria for AML and the ELN 2017 classification criteria)
Duration of Response
Duration of Response (Disease assessment in accordance with the IWG criteria for AML and the ELN 2017 classification criteria)

Full Information

First Posted
March 22, 2023
Last Updated
July 10, 2023
Sponsor
Affimed GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT05817058
Brief Title
First-in-Human Dose Escalation Study of AFM28 in Patients With Relapsed/Refractory Acute Myeloid Leukemia
Official Title
A Phase 1 Multicenter, Open Label, First-in-Human Dose Escalation Study of AFM28, a Bispecific ICE® That Targets CD123 and CD16A, in Patients With CD123-Positive Relapsed/Refractory Acute Myeloid Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 21, 2023 (Actual)
Primary Completion Date
March 2025 (Anticipated)
Study Completion Date
March 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Affimed GmbH

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study is a First In Human, phase 1, open-label, non-randomized, multi-center, multiple ascending dose escalation study evaluating AFM28 as a monotherapy in subjects with Relapsed/Refractory CD123-positive Acute Myeloid Leukemia (AML). AFM28 is a tetravalent monoclonal antibody targeting the interleukin-3 receptor subunit alpha (IL3RA, CD123) and the low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A, CD16A). It is developed as an antineoplastic agent for hematologic malignancies known to express CD123. The primary pharmacological Mode of Action of AFM28 is induction of cell death of CD123-expressing cells by stimulating Antibody-Dependent Cell-mediated Cytotoxicity mediated by CD16A-expressing immune cells, primarily Natural Killer cells. The aim of the dose escalation is to determine the Maximum Tolerated Dose (MTD) and/or establish one or more Recommended Phase 2 Doses, based on safety, preliminary anti-leukemic activity and Pharmacokinetics / Pharmacodynamics data.
Detailed Description
The study drug will be given by intravenous infusion once weekly as long as the subject is deriving clinical benefit until disease progression or other treatment discontinuation criteria met, unacceptable toxicity, or subject's refusal, whichever occurs first. The dose-limiting toxicity observation period will be 28 days, reflecting adequate exposure for safety assessment. The dose-escalation scheme will follow a Bayesian logistic regression model. A safety review committee will monitor safety and recommend all cohort dosing decisions. The starting First In Human dose for AFM28 will be 25 mg i.v. and treatment in each cohort will utilize a staggered approach, with at least 7 days between the first dose of the first subject and the first dose of subsequent subjects. In order to gather additional Pharmacokinetics/ Pharmacodynamics and safety data to inform potential final dose escalation decisions and selection of one or more recommended phase 2 doses at selected dose levels, additional subjects may be enrolled in at least two cohorts consistent with backfilling a cohort (up to 12 subjects).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment of escalating doses of AFM28
Arm Type
Experimental
Arm Description
AFM28 first in human starting dose will be 25 mg i.v.
Intervention Type
Drug
Intervention Name(s)
AFM28
Intervention Description
AFM28 dose escalation
Primary Outcome Measure Information:
Title
The Incidence of dose limiting toxicities
Description
The incidence of dose limiting toxicities during dose limiting toxicities observation period considering the totality of treatment-emergent adverse events is evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events, v5.0 the American Society of Transplantation and Cellular Therapy Cytokine Release Syndrome grading system for Cytokine Release Syndrome the Cairo-Bishop Tumor Lysing Syndrom (TLS) grading system for TLS
Time Frame
28 days following the first dose of study treatment
Secondary Outcome Measure Information:
Title
Incidence and severity of Treatment Emergent Adverse Events
Description
Incidence and severity of Treatment Emergent Adverse Events
Time Frame
through study completion (up to 36 weeks)
Title
Incidence and severity of Serious Adverse Events
Description
Incidence and severity of Serious Adverse Events
Time Frame
through study completion (up to 36 weeks)
Title
Incidence of subjects developing anti-drug antibodies
Description
Incidence of anti-drug antibodies during treatment with AFM28 (by measurement of anti-drug antibodies before and throughout treatment with AFM28)
Time Frame
through study completion (up to 36 weeks)
Title
Area under the concentration-time curve
Description
Area under the concentration-time curve over the dose interval
Time Frame
cycle 1 (day 1 and day 28)
Title
Cmax
Description
Maximum observed plasma concentration
Time Frame
cycle 1 (day 1 and day 28)
Title
Tmax
Description
Time to reach maximum observed plasma concentration
Time Frame
cycle 1 (day 1 and day 28)
Title
Ctrough
Description
Concentration measured immediately prior to the fourth dose
Time Frame
immediately prior to the fourth dose
Title
Complete Response
Description
Complete response (Disease assessment in accordance with the International Working Group (IWG) criteria for AML and the European Leukemia Network (ELN) 2017 classification criteria)
Time Frame
Through treatment period until 14 days after last dose
Title
Complete Response hematological
Description
Complete Response with partial hematologic recovery (Disease assessment in accordance with the IWG criteria for AML and the ELN 2017 classification criteria)
Time Frame
Through treatment period until 14 days after last dose
Title
Complete Response composite rate
Description
Composite complete response rate (Disease assessment in accordance with the IWG criteria for AML and the ELN 2017 classification criteria)
Time Frame
Through treatment period until 14 days after last dose
Title
Complete Response + Complete Response hematological rate
Description
Complete Response plus Complete Response with partial hematologic recovery rate (Disease assessment in accordance with the IWG criteria for AML and the ELN 2017 classification criteria)
Time Frame
Through treatment period until 14 days after last dose
Title
Overall Response Rate
Description
Overall response rate (Disease assessment in accordance with the IWG criteria for AML and the ELN 2017 classification criteria)
Time Frame
Through treatment period until 14 days after last dose
Title
Disease Control Rate
Description
Disease control rate (Disease assessment in accordance with the IWG criteria for AML and the ELN 2017 classification criteria)
Time Frame
Through treatment period until 14 days after last dose
Title
Duration of Response
Description
Duration of Response (Disease assessment in accordance with the IWG criteria for AML and the ELN 2017 classification criteria)
Time Frame
Through treatment period until 14 days after last dose

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 1. Subjects with a confirmed diagnosis of AML as defined by 2016 WHO Classification and determined by pathology review at the study site. Subjects with acute promyelocytic leukemia are excluded. 2. Subjects must have CD123-positive AML confirmed on bone marrow or peripheral blood at Screening (assessed locally without any cut-off level). 3. Subjects with AML who are in the first, second, or third relapse OR who are at least primary refractory and received at most 3 regimes of previous standard anti-leukemia therapy. 4. Primary refractory is defined as ≥ 5% blasts in bone marrow following 2 cycles of anthracycline and cytarabine based induction (such as 3+7 or similar), or one cycle of purine analogue containing induction, or after ≥ 3 cycles hypomethylating agent ± or low dose cytarabine ± B-Cell lymphoma 2 based induction regimen, or ≥ 4 cycles of hypomethylating agent based therapy. 5. Subjects with prior autologous and allogeneic bone marrow transplant are eligible. Subjects with an allogeneic transplant must meet the following conditions: The transplant must have been performed > 3 months before the date of dosing on this study, the subject must not have active graft versus host disease, must be off all graft versus host disease medications at least > 28 days prior to date of dosing of study drug (for example, calcineurin inhibitors, ≥ 10 mg/day prednisone or other steroid equivalent, or other immunosuppressive agents). Exclusion Criteria: 1. Diagnosis of BCR-ABL-positive leukemia, acute promyelocytic leukemia, or juvenile myelomonocytic leukemia. 2. Known hypersensitivity/allergic reaction ≥ grade 3 to monoclonal antibodies or any components used in the AFM28 drug product preparation, any history of anaphylaxis or uncontrolled asthma. Prior CD123 targeting therapies should be allowed after discussion with and at the discretion of the Sponsor. 3. Received any anticancer therapy or investigational treatment for AML within 14 days of the first dose of study drug and within 28 days for biological agents including but not limited to monoclonal antibodies, cellular therapies, bispecific antibodies, checkpoint antibodies and others. Must have recovered to grade ≤ 1 from any grade 2 to 4 toxicity from previous treatment, except alopecia. 4. History of any other systemic malignancy, unless previously treated with curative intent and the subject has been disease free for 2 years or longer. Examples for acceptable previous malignancies include completely removed in situ cervical intra-epithelial neoplasia, non-melanoma skin cancer, ductal carcinoma in situ, early-stage prostate cancer that has been adequately treated. Subjects who meet the above criteria and are on maintenance therapy for the prior malignancy may be eligible after discussion and approval from the medical monitor. 5. The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment. 6. Known clinically active or suspected central nervous system (CNS) leukemia. If suspected, CNS leukemia should be ruled out with relevant imaging and/or examination of cerebrospinal fluid. Subjects with known prior CNS leukemia should have had at least two consecutive negative Lumbar Punctures for CNS leukemia and no clinical signs.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Affimed GmbH
Phone
+49 6221 6743
Ext
60
Email
trials@affimed.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lydia Wunderle
Organizational Affiliation
Affimed GmbH
Official's Role
Study Director
Facility Information:
Facility Name
Institut Universitaire du Cancer Toulouse - Oncopole
City
Toulouse
ZIP/Postal Code
31059
Country
France
Individual Site Status
Active, not recruiting
Facility Name
Institut Català d'Oncologia-Hospital Duran i Reynals
City
Barcelona
ZIP/Postal Code
08907
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Montserrat Arnan Sangerman, MD, PhD
Facility Name
Hospital Universitario 12 de Octubre
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Individual Site Status
Active, not recruiting
Facility Name
Hospital Universitari i Politècnic La Fe
City
Valencia
ZIP/Postal Code
CP 46026
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Pau Montesinos, MD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

First-in-Human Dose Escalation Study of AFM28 in Patients With Relapsed/Refractory Acute Myeloid Leukemia

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