Study of KB004 in Subjects With Hematologic Malignancies (Myelodysplastic Syndrome, MDS, Myelofibrosis, MF)

Study Overview
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Brief Summary
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This is a global, multicenter, open-label, repeat-dose, Phase 1/2 study consisting of a Dose Escalation Phase (Phase 1) and a Cohort Expansion Phase (Phase 2). In both phases, KB004 will be administered by IV infusion once weekly as part of a 21-day dosing cycle.

Detailed Description
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The purpose of Phase 1 is to determine a maximum tolerated dose (MTD) for KB004 when administered to subjects with hematologic malignancies who meet the entry criteria. Phase 1 has completed enrollment July of 2014, the recommended Phase 2 dose is 250 mg. AML 20 mg Cohort completed enrollment Dec 2014. The purpose of Phase 2 is to characterize preliminary clinical activity. The Phase 2 portion of the study consists of two parts: Part A: Subjects with AML or MDS who meet the entry criteria Part B: Subjects with MF who meet the entry criteria

Official Title
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Study of the Anti-EphA3 Monoclonal Antibody KB004 in Subjects With EphA3-Expressing Hematologic Malignancies

Conditions
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Myelodysplastic Syndrome (MDS), Myelofibrosis (MF)

Intervention / Treatment
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* Drug: KB004, Monoclonal Antibody


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria (Phase 1): - Confirmed hematologic malignancy, including Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Acute Lymphocytic Leukemia (ALL), Myelodysplastic Syndrome (MDS), Multiple Myeloma (MM), Myelofibrosis (MF), Myeloproliferative Neoplasms (MPN) or MDS/MPN overlap diseases. (Once Phase 2 has started subjects with AML will be eligible for inclusion in the Phase 1 portion of the study only if their malignancy has been shown to have c-Cbl mutation, trisomy 3, trisomy 11, inv(16), or elevated FLT3. [Other AML and subjects with MDS will no longer be eligible for inclusion in the Phase 1 portion of the study]). Key Inclusion Criteria (Phase 2): Part A: AML or MDS patients with an acceptable level of EphA3 expression Part B: MF patients with an acceptable level of EphA3 expression Key Inclusion Criteria (Both Phases): Confirmed hematologic malignancy refractory to or progressed following standard treatments, or subjects not considered medically suitable to receive standard of care treatment or who refuse standard of care treatment Acceptable level of EphA3 expression Eastern Cooperative Oncology Group (ECOG) ≤1 Acceptable laboratory results Key Exclusion Criteria (Both Phases): For subjects with AML, more than 2 prior therapies for AML (induction and consolidation with or without a hypomethylating agent given in a maintenance setting are considered 1 therapy) History of or current central nervous system (CNS) involvement that may increase risk of bleeding Recent major surgery Ongoing surgical or wound healing complications Active clinically significant bleeding Uncontrolled hypertension Significant intercurrent illness Known history of prolonged bleeding times or platelet dysfunction Active infection requiring IV antibiotics, IV antifungals, or IV antivirals within 2 weeks prior to Cycle 1, Day 1

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 dose levels: KB004<br>IV infusion 1x Weekly for a 21 day dosing cycle Subjects with heme malignancies will be assigned to one of 11 planned KB004 (dose levels (20mg, 40mg, 70mg, 100mg, 140mg, 190mg, 250mg, 330mg) | Drug: KB004, Monoclonal Antibody<br> <br> |
| Experimental: Phase 2 dose levels: KB004<br>IV infusion 1x Weekly for a 21 day dosing cycle Subjects will be assigned to the recommended Phase 2 dose of 250 mg | Drug: KB004, Monoclonal Antibody<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Determine a possible maximum tolerated dose (MTD) |  | Once weekly for the first three weeks of study treatment | 
| Phase 2: To characterize preliminary clinical activity based on the International Working Group (IWG) criteria specific to the hematologic malignancy |  | Evaluations at designated timepoints | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Examine clinical activity |  | Evaluations at designated timepoints | 
| Phase 1/2: Safety and Tolerability |  | Duration of study participation | 
| Phase 1/2: Pharmacokinetic profile |  | Cycle 1: multiple timepoints. Thereafter, single samples at designated cycles | 
| Phase 1/2: Assess immunogenicity |  | Cycle 1: multiple timepoints. Thereafter, single samples at designated cycles | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematologic, Leukemia, Malignancies, Myeloproliferative Neoplasms