Myeloid Leukemia
Conditions
Keywords
AML, Leukemia, Acute Myeloid Leukemia, Antibodies, Monoclonal
Brief summary
The purpose of this study is to determine if IMC-EB10 is safe for participants with leukemia, and also to determine the best dose of IMC-EB10 to give to participants.
Detailed description
The purpose of this study is to define the maximum tolerated dose (MTD) and the pharmacokinetic (PK) profile of the anti-FMS-like tyrosine kinase 3 (FLT3) monoclonal antibody IMC-EB10, administered weekly in participant with acute lymphoblastic leukemia (AML) who have failed to achieve complete remission to a standard induction regimen, relapsed after response to previous antileukemia therapy, or are not eligible for potentially curative or approved salvage options.
Interventions
BIOLOGICALIMC-EB10
Cohort 1 will receive IMC-EB10 intravenously for 3 weekly infusions, followed by a 1-week observation period. The starting dose in Cohort 1 will be 5 mg/kg. After all participants in Cohort 1 complete the first cycle of therapy, dose escalation for subsequent cohorts will proceed as follows: Cohort 2 - 10 mg/kg, Cohort 3 - 20 mg/kg, Cohort 4 - 30 mg/kg. Participants who experience a dose-limiting toxicity (DLT) will not receive further IMC-EB10 treatment, but will continue to be followed on the protocol. Participants may continue to receive IMC-EB10 therapy, in the absence of treatment failure, treatment intolerance, or other withdrawal criteria for additional 28-day cycles at the same dose that they initially received. Dosing for Cycle 2 and beyond will be administered on Days 1, 8, 15, and 22 of a 28-day treatment cycle
Sponsors
Eli Lilly and Company
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. The participant has acute myeloid leukemia in the bone marrow or blood that has relapsed with or without a prior complete remission 2. The participant is not regarded to be a candidate for a potentially curative, higher priority treatment for acute myeloid leukemia 3. The participant has resolution of all clinically significant toxic effects of any prior antitumor therapy and any other study-specific clinical or laboratory parameter specified in the entry criteria 4. The participant has not had major surgery, an open biopsy, a significant injury, and/or prior antitumor therapy (except antileukemia therapy) within 21 days prior to the first infusion of IMC-EB10 5. The participant has an Eastern Cooperative Oncology Group (ECOG)performance status of 0, 1, or 2 at study entry. 6. The participant is age 18 years or older 7. The participant has a life expectancy of \>3 months 8. The participant has adequate liver and kidney function, as defined in the entry criteria 9. The participant is using an effective contraception (per the institutional standard), if procreative potential exists 10. The participant is able to give written informed consent 11. The participant is willing and able to comply with study procedures, scheduled visits, and treatment plans
Exclusion criteria
1. The participant has had prior allogenic or autologous stem cell transplant within \<3 months of the first infusion of IMC-EB10 2. The participant has had an organ transplant (nonhematologic) within 3 years of study entry 3. The participant has active central nervous system leukemia 4. The participant has extramedullary disease without peripheral/and or bone marrow involvement 5. The participant is disease-free from a previous or concurrent malignancy for a period ≤ 1 year. A participant who has basal cell carcinoma or carcinoma in situ of the cervix will not be excluded from the study 6. The participant is currently receiving antileukemia therapy. Concurrent treatment with hydroxyurea is permitted 7. The participant has uncontrolled intercurrent illness as specified in the study entry criteria 8. The participant is receiving chronic steroid or other immunosuppressive medications. Occasional use of steroid-containing medications for, for example (e.g.), asthma exacerbation or for skin lesions, is permitted 9. The participant is receiving full-dose heparin (including low molecular weight heparin) or warfarin. \[The participant is permitted to use low-dose warfarin to maintain patency of preexisting, permanent, indwelling intravenous (I.V.) catheters.\] 10. The participant is pregnant (confirmed by urine or serum pregnancy test) or breast feeding 11. The participant has received treatment with monoclonal antibodies within 6 weeks prior to first infusion of IMC-EB10 12. The participant has a history of clinically significant allergic reactions to monoclonal antibodies or other therapeutic proteins
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerate Dose (MTD) of IMC-EB10 | Cycle 1 (28-day cycle) | MTD is defined as the dose preceding the dose level at which 2 participants experienced a dose limiting toxicity (DLT) during Cycle 1. DLT is defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI-CTCAE v 3.0): (1) any Grade 3 or 4 toxicity that is clearly not attributable to leukemia \[for example (e.g.) a type of end-organ failure that is infrequently encountered in acute myeloid leukemia (AML)\] and is possibly, probably, or definitely attributable to IMC-EB10 in the judgment of the investigator; and (2) any Grade 3 or 4 toxicity that is clearly not attributable to a co-medication (e.g., prolonged neutropenia that is not attributable to hydroxyurea). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK: Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Concentration [AUC(0-last)] | Cycle 1 Week 1: predose, immediately after infusion, and at 1.5, 2, 4, 8, 24, 96 and 168 h after infusion ends (28-day cycle) | — |
| PK: Area Under the Concentration Time Curve During the Dosing Interval (AUCtau) Where Tau is 168 Hours | Cycle 1 Week 3: predose, immediately after infusion and at 1.5, 2, 4, 8, 24, 48, 96,168, 240 and 336 h after infusion ends (28-day cycle) | — |
| Number of Participants With Adverse Events (AEs) (Safety Profile of IMC-EB10) | 8 weeks and 30-day post-treatment follow-up | Clinically significant events were defined as serious adverse events (SAEs) and other non-serious AEs regardless of causality. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module |
| Pharmacokinetic (PK): Maximum Concentration (Cmax) | Cycle 1 Week 1: predose, immediately after infusion, and 1.5, 2, 4, 8, 24, 96, and 168 h after infusion ends, and Cycle 1 Week 3: predose, immediately after infusion, and 1.5, 2, 4, 8, 24, 48, 96,168, 240 and 336 h after infusion ends (28-day cycles) | — |
| Number of Participants With Antileukemic Complete Response (CR) or Partial Response (PR) | 4 weeks | Assessment of antileukemic response was based on hematologic response criteria. PR defined as \>1000/microliter (µL) neutrophils and ≥100000/µL platelets in peripheral blood; a decrease of ≥50% in the pretreatment percentage of blasts to 5% to 25% in the bone marrow aspirate or a value of ≤5% blasts if Auer rods are present. Cytogenetic CR defined as normal cytogenetic findings. Molecular CR defined as negative findings for minimal residual disease by automated quantitative Reverse-Transcription-Polymerase Chain Reaction (RT-PCR) and multidimensional flow cytometry. Morphologic CR with incomplete blood count recovery defined as ≤5% blasts (containing no Auer rods) in a bone marrow aspirate with spicules; neutrophil count \< 1000/µL or platelets \<100000/mL in peripheral blood or no extramedullary leukemia present. |
| Number of Participants With Feline McDonough Sarcoma (FMS)-Like Tyrosine Kinase 3 (FLT3) Response | Week 4 and Week 8 | FLT3 response to IMC-EB10 is defined as wild type, internal tandem duplications (ITD) mutations and other mutations. |
| Number of Participants With Anti-IMC-EB10 Antibodies | Cycle 1, Weeks 1 and 3 and Cycle 2, Week 1: predose (28-day cycles) | A participant is considered positive for antibodies against IMC-EB10 if their blood sample exhibited a post-treatment antibody level that exceeds the positive upper cut point determined from the anti-IMC-EB10 level in healthy untreated individuals. A participant was considered to have an anti-IMC-EB10 response if there are 2 consecutive positive samples or if the final sample tested is positive. |
Countries
United States
Participant flow
Pre-assignment details
Participant Flow is reporting enrolled participants who discontinued from the study. Participants who died or had progressive disease (PD) were considered to have completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - 5mg/kg IMC-EB10 IMC-EB10: 5 mg/kg administered IV on Days 1, 8, and 15 of Cycle 1 (28-day cycle) and Days 1, 8, 15, and 22 of subsequent 28-day cycles. | 3 |
| Cohort 2 - 10 mg/kg IMC-EB10 IMC-EB10: 10 mg/kg administered IV on Days 1, 8, and 15 of Cycle 1 (28-day cycle) and Days 1, 8, 15, and 22 of subsequent 28-day cycles. | 13 |
| Cohort 3 - 20 mg/kg IMC-EB10 IMC-EB10: 20 mg/kg administered IV on Days 1, 8, and 15 of Cycle 1 (28-day cycle) and Days 1, 8, 15, and 22 of subsequent 28-day cycles. | 3 |
| Cohort 4 - 30 mg/kg IMC-EB10 IMC-EB10: 30 mg/kg administered IV on Days 1, 8, and 15 of Cycle 1 (28-day cycle) and Days 1, 8, 15, and 22 of subsequent 28-day cycles. | 5 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 - 5mg/kg IMC-EB10 | Total | Cohort 4 - 30 mg/kg IMC-EB10 | Cohort 3 - 20 mg/kg IMC-EB10 | Cohort 2 - 10 mg/kg IMC-EB10 |
|---|---|---|---|---|---|
| Age, Continuous | 67.7 years STANDARD_DEVIATION 5.97 | 65.0 years STANDARD_DEVIATION 15.89 | 60.3 years STANDARD_DEVIATION 16.91 | 74.8 years STANDARD_DEVIATION 4.45 | 63.9 years STANDARD_DEVIATION 18.52 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 19 Participants | 3 Participants | 3 Participants | 10 Participants |
| Region of Enrollment United States | 3 Participants | 24 Participants | 5 Participants | 3 Participants | 13 Participants |
| Sex: Female, Male Female | 0 Participants | 10 Participants | 1 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Male | 3 Participants | 14 Participants | 4 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 11 / 13 | 3 / 3 | 5 / 5 |
| serious Total, serious adverse events | 1 / 3 | 7 / 13 | 1 / 3 | 3 / 5 |
Outcome results
Primary
Maximum Tolerate Dose (MTD) of IMC-EB10
MTD is defined as the dose preceding the dose level at which 2 participants experienced a dose limiting toxicity (DLT) during Cycle 1. DLT is defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI-CTCAE v 3.0): (1) any Grade 3 or 4 toxicity that is clearly not attributable to leukemia \[for example (e.g.) a type of end-organ failure that is infrequently encountered in acute myeloid leukemia (AML)\] and is possibly, probably, or definitely attributable to IMC-EB10 in the judgment of the investigator; and (2) any Grade 3 or 4 toxicity that is clearly not attributable to a co-medication (e.g., prolonged neutropenia that is not attributable to hydroxyurea).
Time frame: Cycle 1 (28-day cycle)
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-EB10 5 to 30 mg/kg | Maximum Tolerate Dose (MTD) of IMC-EB10 | NA mg/kg |
Secondary
Number of Participants With Adverse Events (AEs) (Safety Profile of IMC-EB10)
Clinically significant events were defined as serious adverse events (SAEs) and other non-serious AEs regardless of causality. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module
Time frame: 8 weeks and 30-day post-treatment follow-up
Population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMC-EB10 5 to 30 mg/kg | Number of Participants With Adverse Events (AEs) (Safety Profile of IMC-EB10) | SAEs | 1 participants |
| IMC-EB10 5 to 30 mg/kg | Number of Participants With Adverse Events (AEs) (Safety Profile of IMC-EB10) | Other Non-Serious AEs | 3 participants |
| Cohort 2 - 10 mg/kg IMC-EB10 | Number of Participants With Adverse Events (AEs) (Safety Profile of IMC-EB10) | Other Non-Serious AEs | 11 participants |
| Cohort 2 - 10 mg/kg IMC-EB10 | Number of Participants With Adverse Events (AEs) (Safety Profile of IMC-EB10) | SAEs | 7 participants |
| Cohort 3 - 20 mg/kg IMC-EB10 | Number of Participants With Adverse Events (AEs) (Safety Profile of IMC-EB10) | Other Non-Serious AEs | 3 participants |
| Cohort 3 - 20 mg/kg IMC-EB10 | Number of Participants With Adverse Events (AEs) (Safety Profile of IMC-EB10) | SAEs | 1 participants |
| Cohort 4 - 30 mg/kg IMC-EB10 | Number of Participants With Adverse Events (AEs) (Safety Profile of IMC-EB10) | Other Non-Serious AEs | 5 participants |
| Cohort 4 - 30 mg/kg IMC-EB10 | Number of Participants With Adverse Events (AEs) (Safety Profile of IMC-EB10) | SAEs | 3 participants |
Secondary
Number of Participants With Anti-IMC-EB10 Antibodies
A participant is considered positive for antibodies against IMC-EB10 if their blood sample exhibited a post-treatment antibody level that exceeds the positive upper cut point determined from the anti-IMC-EB10 level in healthy untreated individuals. A participant was considered to have an anti-IMC-EB10 response if there are 2 consecutive positive samples or if the final sample tested is positive.
Time frame: Cycle 1, Weeks 1 and 3 and Cycle 2, Week 1: predose (28-day cycles)
Population: Zero participants were analyzed. The study was discontinued early due to lack of efficacy and no data was collected.
Secondary
Number of Participants With Antileukemic Complete Response (CR) or Partial Response (PR)
Assessment of antileukemic response was based on hematologic response criteria. PR defined as \>1000/microliter (µL) neutrophils and ≥100000/µL platelets in peripheral blood; a decrease of ≥50% in the pretreatment percentage of blasts to 5% to 25% in the bone marrow aspirate or a value of ≤5% blasts if Auer rods are present. Cytogenetic CR defined as normal cytogenetic findings. Molecular CR defined as negative findings for minimal residual disease by automated quantitative Reverse-Transcription-Polymerase Chain Reaction (RT-PCR) and multidimensional flow cytometry. Morphologic CR with incomplete blood count recovery defined as ≤5% blasts (containing no Auer rods) in a bone marrow aspirate with spicules; neutrophil count \< 1000/µL or platelets \<100000/mL in peripheral blood or no extramedullary leukemia present.
Time frame: 4 weeks
Population: All randomized participants who received at least 1 dose of study drug.No anti-leukemic responses were observed as there were no responders due to high rate of treatment failures and were not evaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-EB10 5 to 30 mg/kg | Number of Participants With Antileukemic Complete Response (CR) or Partial Response (PR) | 0 participants |
| Cohort 2 - 10 mg/kg IMC-EB10 | Number of Participants With Antileukemic Complete Response (CR) or Partial Response (PR) | 0 participants |
| Cohort 3 - 20 mg/kg IMC-EB10 | Number of Participants With Antileukemic Complete Response (CR) or Partial Response (PR) | 0 participants |
| Cohort 4 - 30 mg/kg IMC-EB10 | Number of Participants With Antileukemic Complete Response (CR) or Partial Response (PR) | 0 participants |
Secondary
Number of Participants With Feline McDonough Sarcoma (FMS)-Like Tyrosine Kinase 3 (FLT3) Response
FLT3 response to IMC-EB10 is defined as wild type, internal tandem duplications (ITD) mutations and other mutations.
Time frame: Week 4 and Week 8
Population: All randomized participants who received at least 1 dose of study drug. No tyrosine kinase responses were observed as there were no responders due to high rate of treatment failures and were not evaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-EB10 5 to 30 mg/kg | Number of Participants With Feline McDonough Sarcoma (FMS)-Like Tyrosine Kinase 3 (FLT3) Response | 0 participants |
| Cohort 2 - 10 mg/kg IMC-EB10 | Number of Participants With Feline McDonough Sarcoma (FMS)-Like Tyrosine Kinase 3 (FLT3) Response | 0 participants |
| Cohort 3 - 20 mg/kg IMC-EB10 | Number of Participants With Feline McDonough Sarcoma (FMS)-Like Tyrosine Kinase 3 (FLT3) Response | 0 participants |
| Cohort 4 - 30 mg/kg IMC-EB10 | Number of Participants With Feline McDonough Sarcoma (FMS)-Like Tyrosine Kinase 3 (FLT3) Response | 0 participants |
Secondary
Pharmacokinetic (PK): Maximum Concentration (Cmax)
Time frame: Cycle 1 Week 1: predose, immediately after infusion, and 1.5, 2, 4, 8, 24, 96, and 168 h after infusion ends, and Cycle 1 Week 3: predose, immediately after infusion, and 1.5, 2, 4, 8, 24, 48, 96,168, 240 and 336 h after infusion ends (28-day cycles)
Population: All randomized participants with Cmax results.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| IMC-EB10 5 to 30 mg/kg | Pharmacokinetic (PK): Maximum Concentration (Cmax) | Week 1 | 129 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 25 |
| IMC-EB10 5 to 30 mg/kg | Pharmacokinetic (PK): Maximum Concentration (Cmax) | Week 3 | 119 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 24 |
| Cohort 2 - 10 mg/kg IMC-EB10 | Pharmacokinetic (PK): Maximum Concentration (Cmax) | Week 3 | 781 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 66 |
| Cohort 2 - 10 mg/kg IMC-EB10 | Pharmacokinetic (PK): Maximum Concentration (Cmax) | Week 1 | 254 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 35 |
| Cohort 3 - 20 mg/kg IMC-EB10 | Pharmacokinetic (PK): Maximum Concentration (Cmax) | Week 3 | 1520 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 9 |
| Cohort 3 - 20 mg/kg IMC-EB10 | Pharmacokinetic (PK): Maximum Concentration (Cmax) | Week 1 | 896 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 30 |
| Cohort 4 - 30 mg/kg IMC-EB10 | Pharmacokinetic (PK): Maximum Concentration (Cmax) | Week 1 | 927 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 38 |
| Cohort 4 - 30 mg/kg IMC-EB10 | Pharmacokinetic (PK): Maximum Concentration (Cmax) | Week 3 | 1770 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 74 |
Secondary
PK: Area Under the Concentration Time Curve During the Dosing Interval (AUCtau) Where Tau is 168 Hours
Time frame: Cycle 1 Week 3: predose, immediately after infusion and at 1.5, 2, 4, 8, 24, 48, 96,168, 240 and 336 h after infusion ends (28-day cycle)
Population: All randomized participants with AUCtau results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IMC-EB10 5 to 30 mg/kg | PK: Area Under the Concentration Time Curve During the Dosing Interval (AUCtau) Where Tau is 168 Hours | NA µg*h/mL | — |
| Cohort 2 - 10 mg/kg IMC-EB10 | PK: Area Under the Concentration Time Curve During the Dosing Interval (AUCtau) Where Tau is 168 Hours | 72500 µg*h/mL | Geometric Coefficient of Variation 41 |
| Cohort 3 - 20 mg/kg IMC-EB10 | PK: Area Under the Concentration Time Curve During the Dosing Interval (AUCtau) Where Tau is 168 Hours | 108000 µg*h/mL | Geometric Coefficient of Variation 39 |
| Cohort 4 - 30 mg/kg IMC-EB10 | PK: Area Under the Concentration Time Curve During the Dosing Interval (AUCtau) Where Tau is 168 Hours | NA µg*h/mL | — |
Secondary
PK: Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Concentration [AUC(0-last)]
Time frame: Cycle 1 Week 1: predose, immediately after infusion, and at 1.5, 2, 4, 8, 24, 96 and 168 h after infusion ends (28-day cycle)
Population: All randomized participants with AUC(0-last) results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IMC-EB10 5 to 30 mg/kg | PK: Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Concentration [AUC(0-last)] | 9090 micrograms * hours/milliliter (µg*h/mL) | Geometric Coefficient of Variation 39 |
| Cohort 2 - 10 mg/kg IMC-EB10 | PK: Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Concentration [AUC(0-last)] | 23300 micrograms * hours/milliliter (µg*h/mL) | Geometric Coefficient of Variation 27 |
| Cohort 3 - 20 mg/kg IMC-EB10 | PK: Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Concentration [AUC(0-last)] | 71800 micrograms * hours/milliliter (µg*h/mL) | Geometric Coefficient of Variation 40 |
| Cohort 4 - 30 mg/kg IMC-EB10 | PK: Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Concentration [AUC(0-last)] | 77200 micrograms * hours/milliliter (µg*h/mL) | Geometric Coefficient of Variation 69 |