Post-transplant Flotetuzumab for AML

NCT ID: NCT05506956

Last Updated: 2025-09-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-10-20
• Study Completion Date: 2024-06-18

Brief Summary

The purpose of this research study is to determine if the study drug, flotetuzumab, is safe and tolerable when given to participants with acute myeloid leukemia (AML) that has relapsed after transplant.

Detailed Description

Despite significant advances, the prognosis for patients with AML remains poor with 5-year overall survival of just ~40% in younger patients and much poorer long-term survival in older patients. Allogeneic hematopoietic stem cell transplantation (AlloHSCT) as post-remission therapy has led to improved overall survival when compared to consolidation chemotherapy for the vast majority of AML patients who have intermediate or poor risk cytogenetics. Due to significant transplant-related mortality (TRM) and poor outcomes in older patients with myeloablative conditioning (MAC) transplantation, there have been many studies investigating the feasibility of less intensive conditioning regimens such as reduced-intensity conditioning (RIC) and nonmyeloablative (NMA), which have shown comparable overall survival with decreased TRM but an increased risk of relapse. As these less intensive conditioning strategies become more widely adopted, the need to focus on the identification and treatment of AML patients at risk for post-transplant relapse increases. Maintenance therapy with tyrosine kinase inhibitors and monoclonal antibodies have proven safe and effective across a range of diseases including AML, acute lymphocytic leukemia (ALL), and non-Hodgkin's lymphoma (NHL). Leukemia stem cells (LSCs) are another potential target for post-transplant therapy, and the expression of CD123 readily discriminates AML LSCs from hematopoietic stem cells (HSCs). The anti-CD123 monoclonal antibody CSL360 has previously demonstrated efficacy in post-transplant patients with relapsed disease, while flotetuzumab has demonstrated efficacy in relapsed and refractory patients. Given this preliminary data, the investigators propose a trial of flotetuzumab as post-alloHSCT therapy for AML in patients with evidence of disease post-transplant including frank relapse. The investigators believe that treatment with flotetuzumab in this setting will be well tolerated and effective. Flotetuzumab is not approved for use in people with AML. Its use has not been specifically studied in patients with AML following a bone marrow transplant and therefore its use in this study is investigational.

Conditions

Leukemia, Myeloid, Acute

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Flotetuzumab Following Allogeneic Transplant

All participants will receive one cycle (28 days) of flotetuzumab. After one cycle, all participants will undergo a bone marrow biopsy to assess response and based on the response, may receive additional cycles up to a total cycle of six cycles.

Group Type: EXPERIMENTAL

Flotetuzumab

Intervention Type: DRUG

Patients enrolled on dose level 1 (DL1) will receive flotetuzumab by continuous infusion using multi-step lead-in dosing, and then 500 ng/kg/day on days 7-28. After one cycle, all patients will undergo a bone marrow biopsy to assess response including assessment of minimal residual disease (MRD). Patients who fail to achieve a CR, CRi, CRh (complete remission with partial hematologic recovery), or MLFS may continue with subsequent induction cycles as a continuous infusion up to a total of five cycles. If there is evidence of response (CR, CRi, CRh, or MLFS) and the toxicities of treatment are acceptable, patients will be eligible for two consolidation cycles. Additional bone marrow biopsies for response assessment will be performed after the second cycle. If there is a need to de-escalate dosing based on toxicity, then patients will be enrolled on DL-1 using multi-step lead-in dosing, and then 300 ng/kg/day on days 5-28 of the first cycle and days 1-28 of subsequent cycles.

Interventions

Flotetuzumab

Patients enrolled on dose level 1 (DL1) will receive flotetuzumab by continuous infusion using multi-step lead-in dosing, and then 500 ng/kg/day on days 7-28. After one cycle, all patients will undergo a bone marrow biopsy to assess response including assessment of minimal residual disease (MRD). Patients who fail to achieve a CR, CRi, CRh (complete remission with partial hematologic recovery), or MLFS may continue with subsequent induction cycles as a continuous infusion up to a total of five cycles. If there is evidence of response (CR, CRi, CRh, or MLFS) and the toxicities of treatment are acceptable, patients will be eligible for two consolidation cycles. Additional bone marrow biopsies for response assessment will be performed after the second cycle. If there is a need to de-escalate dosing based on toxicity, then patients will be enrolled on DL-1 using multi-step lead-in dosing, and then 300 ng/kg/day on days 5-28 of the first cycle and days 1-28 of subsequent cycles.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. A confirmed prior diagnosis of AML and underwent an alloHSCT as a form of consolidation in a morphologic complete remission

2. ECOG performance status 0-2

3. Ability to give informed consent

4. In agreement to use an effective barrier method of birth control to avoid pregnancy during the study and for a minimum of 30 days after study treatment, for all male and female patients who are fertile

5. Age ≥18 years

6. Prior treatment with a CD123-targeted therapy will be allowed assuming the patient did not have a grade 3 or 4 adverse reaction to prior use of this treatment

7. Normal thyroid function (defined by either a thyroid-stimulating hormone (TSH) within the reference range, a TSH above the reference range with a free T4 within the reference range, or a TSH below the reference range with both a free T4 and total T3 within the reference range) or normal thyroid tests on supplementation or treatment (defined as a TSH within the reference range)

8. Patients should be at least 30 days from transplant with morphologic evidence of disease progression on bone marrow biopsy

9. The presence of a CD123+ AML must be confirmed by flow cytometry with >1% CD123 AML blasts

10. Peripheral blast count ≤20,000/mm3 at time of initiation on Cycle 1 Day 1

Exclusion Criteria

1. No evidence of donor engraftment (100% patient DNA in bone marrow or peripheral blood after alloHSCT based on either an unsorted specimen or CD3 sorted).

2. Active AML in central nervous system (CNS) or testes

3. Patients with active, uncontrolled infection. If an infection is controlled and under treatment, then the patient may become eligible.

4. Patients with active acute or chronic GVHD requiring GVHD therapy (mycophenolate mofetil, tacrolimus, sirolimus, or steroids) within 30 days

5. Patients without active acute or chronic GVHD requiring prophylactic GVHD therapy (mycophenolate mofetil, tacrolimus, sirolimus, or steroids) within 30 days

6. Inadequate end organ function defined as:

• Hepatic-AST, ALT, and alkaline phosphatase > 3.5X upper limit of normal (ULN), bilirubin >2.5X ULN
• Renal-creatinine clearance <60 mL/min using the modified Cockcroft-Gault formula
• Cardiac-Recent myocardial infarction within 6 months, Congestive Heart Failure with ejection fraction (EF) <50%, active pericarditis or myocarditis
• Pulmonary-Need for supplemental oxygen to maintain oxygen saturation >92%
• Adrenal-Adrenal insufficiency requiring physiologically-dosed steroids

7. Women who are pregnant or lactating

8. Previous or known hypersensitivity to biological agents or constituents of flotetuzumab or its source material

9. Concurrent use of any other investigational drugs

10. Uncontrolled infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus or hepatitis C virus (HCV)

11. Any active untreated autoimmune disorders (with the exception of vitiligo, resolved childhood atopic dermatitis, prior Grave's disease now euthyroid clinically with stable supplementation)

12. Previous treatment with radiotherapy or an immunotherapeutic agent in the 14 days prior to study drug administration (Cycle 1 Day 1) or 5 half-lifes, whichever is longer

13. Requirement, at the time of study entry, for concurrent steroids > 10 mg/day of oral prednisone or equivalent, except steroid inhaler, nasal spray, or ophthalmic solution

14. Use of granulocyte colony stimulating or granulocyte-macrophage colony stimulating factor in the 2 weeks prior to study drug administration

15. Prior adverse event with CD123 therapy necessitating therapy discontinuation

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

MacroGenics

INDUSTRY

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jonathan Webster, MD

Role: PRINCIPAL_INVESTIGATOR

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Locations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

IRB00235421

Identifier Type: OTHER

Identifier Source: secondary_id

P01CA015396

Identifier Type: NIH

Identifier Source: secondary_id

View Link

J21134

Identifier Type: -

Identifier Source: org_study_id