Leukemia, Myeloid, Acute
Conditions
Keywords
CD123, AML
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.
Interventions
DRUGFlotetuzumab
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.
Sponsors
MacroGenics
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Flotetuzumab in Patients With Relapsed/Refractory AML Following alloHSCT | 6 months | Number of participants with dose-limiting toxicities (DLTs) at specified dose levels to determine MTD |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response to Flotetuzumab in Patients With Relapsed AML Following Allogeneic Hematopoietic Stem Cell Transplant (alloHSCT) | 6 months | Number of participants with complete response (CR) following alloHSCT. |
| Complete Response With Incomplete Count Recovery to Flotetuzumab in Patients With Relapsed AML Following alloHSCT | 6 months | Number of participants with complete response with incomplete count recovery (CRi) following allogeneic hematopoietic stem cell transplant (alloHSCT). |
| Chronic GVHD Incidence | 6 months | Number of events of chronic GVHD requiring systemic immune suppression |
| Acute Graft-versus-host Disease (GVHD) Incidence | 6 months | Number of safety events defined as CTCAE grade III-IV acute GVHD. |
| Non-relapse Mortality | through study completion, an average of 1 year 8 months | Number of participant deaths without recurrent or progressive disease after allo-HSCT. |
| Partial Response to Flotetuzumab in Patients With Relapsed AML Following alloHSCT | 6 months | Number of participants with partial response (PR) following allogeneic hematopoietic stem cell transplant (alloHSCT). |
Countries
United States
Participant flow
Pre-assignment details
All participants receive dose level 1 (DL1): Flotetuzumab: 500 ng/kg/day. No participants received DL-1: Flotetuzumab: 300 ng/kg/day during the study.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 (DL1): Flotetuzumab: 500 ng/kg/Day 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.
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. | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Dose Level 1 (DL1): Flotetuzumab: 500 ng/kg/Day |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 69 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 3 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 2 / 3 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Flotetuzumab in Patients With Relapsed/Refractory AML Following alloHSCT
Number of participants with dose-limiting toxicities (DLTs) at specified dose levels to determine MTD
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 (DL1): Flotetuzumab: 500 ng/kg/Day | Number of Participants With Dose-limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Flotetuzumab in Patients With Relapsed/Refractory AML Following alloHSCT | 1 Participants |
Secondary
Acute Graft-versus-host Disease (GVHD) Incidence
Number of safety events defined as CTCAE grade III-IV acute GVHD.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1 (DL1): Flotetuzumab: 500 ng/kg/Day | Acute Graft-versus-host Disease (GVHD) Incidence | 0 events |
Secondary
Chronic GVHD Incidence
Number of events of chronic GVHD requiring systemic immune suppression
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1 (DL1): Flotetuzumab: 500 ng/kg/Day | Chronic GVHD Incidence | 0 events |
Secondary
Complete Response to Flotetuzumab in Patients With Relapsed AML Following Allogeneic Hematopoietic Stem Cell Transplant (alloHSCT)
Number of participants with complete response (CR) following alloHSCT.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 (DL1): Flotetuzumab: 500 ng/kg/Day | Complete Response to Flotetuzumab in Patients With Relapsed AML Following Allogeneic Hematopoietic Stem Cell Transplant (alloHSCT) | 0 Participants |
Secondary
Complete Response With Incomplete Count Recovery to Flotetuzumab in Patients With Relapsed AML Following alloHSCT
Number of participants with complete response with incomplete count recovery (CRi) following allogeneic hematopoietic stem cell transplant (alloHSCT).
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 (DL1): Flotetuzumab: 500 ng/kg/Day | Complete Response With Incomplete Count Recovery to Flotetuzumab in Patients With Relapsed AML Following alloHSCT | 0 Participants |
Secondary
Non-relapse Mortality
Number of participant deaths without recurrent or progressive disease after allo-HSCT.
Time frame: through study completion, an average of 1 year 8 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 (DL1): Flotetuzumab: 500 ng/kg/Day | Non-relapse Mortality | 0 Participants |
Secondary
Partial Response to Flotetuzumab in Patients With Relapsed AML Following alloHSCT
Number of participants with partial response (PR) following allogeneic hematopoietic stem cell transplant (alloHSCT).
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 (DL1): Flotetuzumab: 500 ng/kg/Day | Partial Response to Flotetuzumab in Patients With Relapsed AML Following alloHSCT | 0 Participants |