Study of IMC-EB10 in Participant With Leukemia

Study Overview
=================
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.

Official Title
-----------------
An Open-label, Dose Escalation, Phase I Study of IMC-EB10 in Patients With Relapsed or Refractory Acute Myeloid Leukemia

Conditions
-----------------
Myeloid Leukemia

Intervention / Treatment
-----------------
* Biological: IMC-EB10


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The participant has acute myeloid leukemia in the bone marrow or blood that has relapsed with or without a prior complete remission The participant is not regarded to be a candidate for a potentially curative, higher priority treatment for acute myeloid leukemia 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 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 The participant has an Eastern Cooperative Oncology Group (ECOG)performance status of 0, 1, or 2 at study entry. The participant is age 18 years or older The participant has a life expectancy of >3 months The participant has adequate liver and kidney function, as defined in the entry criteria The participant is using an effective contraception (per the institutional standard), if procreative potential exists The participant is able to give written informed consent The participant is willing and able to comply with study procedures, scheduled visits, and treatment plans Exclusion Criteria: The participant has had prior allogenic or autologous stem cell transplant within <3 months of the first infusion of IMC-EB10 The participant has had an organ transplant (nonhematologic) within 3 years of study entry The participant has active central nervous system leukemia The participant has extramedullary disease without peripheral/and or bone marrow involvement 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 The participant is currently receiving antileukemia therapy. Concurrent treatment with hydroxyurea is permitted The participant has uncontrolled intercurrent illness as specified in the study entry criteria 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 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.] The participant is pregnant (confirmed by urine or serum pregnancy test) or breast feeding The participant has received treatment with monoclonal antibodies within 6 weeks prior to first infusion of IMC-EB10 The participant has a history of clinically significant allergic reactions to monoclonal antibodies or other therapeutic proteins

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMC-EB10 5 milligrams/kilogram (mg/kg)<br>All participants will receive intravenous infusions of IMC-EB10, with the dose depending on which cohort they are enrolled into. | Biological: IMC-EB10<br>* 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<br>* Other names: LY3012218;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Cycle 1 (28-day cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 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 | 8 weeks and 30-day post-treatment follow-up | 
| 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. | Cycle 1, Weeks 1 and 3 and Cycle 2, Week 1: predose (28-day cycles) | 
| 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. | 4 weeks | 
| 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. | Week 4 and Week 8 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AML, Leukemia, Acute Myeloid Leukemia, Antibodies, Monoclonal