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

IRB KALO1Z12

CC 13-595

Hospital Main Campus

Phase Phase 2

Disease Leukemia - Acute Myeloid (AML), Myelodisplastic Syndrome (MDS)

Drug KB004

Description

1. Dose Escalation Phase: The primary objective is to determine a possible maximum tolerated dose (MTD, defined in Section 7.1.1) for KB004 when administered up to 700 mg once weekly by IV infusion to subjects with hematologic malignancies.
2. Cohort Expansion Phase: The primary objective is to characterize preliminary clinical activity based on the International Working Group (IWG) criteria specific to the hematologic malignancy, (to qualify, tumors must show measurable expression of EphA3 as assessed by IHC.Secondary Objectives
   1. For the Dose Escalation Phase only, a secondary objective is to characterize the preliminary clinical activity of KB004.
   2. Both Phases:
      • Examine the safety and tolerability profile of KB004
      • Describe the PK profile of KB004
      • Assess the immunogenicity profile of KB004
   Exploratory Objectives
   1. Explore potential diagnostics for EphA3 expression on tumor cells, stromal cells, and endothelial cells, using peripheral blood, bone marrow aspirates, and/or bone marrow biopsies as assessed by RT-PCR
   2. Describe the PD effects of KB004 as assessed by IHC and RT-PCR
   3. Explore correlative pharmacogenomic (PG) information as it might relate to EphA3 expression and KB004 antitumor response
   4. Evaluate the effect of KB004 on the marrow microenvironment, including microvessel density
   5. Evaluate the downstream effect of KB004 on signal transduction

Inclusion Criteria

1. Age ≥18 years
2. 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.

   Dose Escalation Phase

   Confirmed hematologic malignancy including but not limited to AML, CLL, CML, ALL, MDS, MM, MF, MPN, or intermediate-2 or high-risk MDS/MPN overlap diseases.

   Upon initiation of the Cohort Expansion Phase, subjects with AML are eligible for inclusion in the Dose Escalation Phase only if their malignancy previously has been shown to have c-Cbl mutation, trisomy 3, trisomy 11, inv(16), or elevated FLT3.

   Note: Other AML subjects and subjects with MDS will no longer be eligible for inclusion in the Dose Escalation Phase.

   Cohort Expansion Phase

   • Part A: AML or MDS with tumors showing measureable expression of EphA3⁺ (≥10% of EphA3⁺ nucleated cells) as determined by IHC
   • Part B: MF with tumors showing measureable expression of EphA3⁺ (≥10% of EphA3⁺ nucleated cells and/or ≥10% of EphA3⁺ fibroblasts) as determined by IHC. Possibly 1 other confirmed hematologic malignancy (e.g., MM) with tumors showing measureable expression of EphA3⁺ (the expression of EphA3⁺ to be determined by KaloBios from emergent data) as determined by IHC
     • MF: Subjects with confirmed diagnosis of primary myelofibrosis (PMF), polycythemia vera myelofibrosis (PV MF), post-polycythemia vera myelofibrosis (PPV MF), or post-essential thrombocythemia myelofibrosis (PET MF) according to the 2008 revised World Health Organization (WHO) criteria, irrespective of JAK2 mutation status
     • If MM is selected: Subjects with confirmed diagnosis of MM based on Durie-Salmon criteria must also have measurable disease defined as follows:
       • Secretors: Serum monoclonal protein ≥1 gm/dL or ≥200 mg/24-hour urine light chain excretion
       • Nonsecretors: Involved free light chain (FLC) level ≥10 mg/dL, provided serum FLC ratio is abnormal; and/or bone marrow involvement >30%; and/or measurable soft tissue plasmacytoma >2 cm (confirmed by physical examination and/or applicable radiological evaluation, i.e., magnetic resonance imaging [MRI], computed tomography [CT], or positron emission tomography/computed tomography [PET/CT])
3. EphA3 expression as follows:

   Note: Bone marrow biopsy is obtained for both phases. More than 1 sample may be collected (1 for usual standard care, 1 for the purpose of this protocol).

   For MF subjects only, bone marrow aspirate is optional, as determined by Investigator assessment of aspirate feasibility.

   • Dose Escalation Phase:

     Bone marrow aspirate and bone marrow biopsy are obtained for measurement of EphA3 expression unless prior approval is obtained from KaloBios.

   • Cohort Expansion Phase:

     Bone marrow biopsy sample for EphA3 expression as determined by IHC. KaloBios may increase or decrease this cut-off level on EphA3 expression as additional data are accumulated.

4. Eastern Cooperative Oncology Group (ECOG) (Appendix C) performance status ≤1.
5. The following local laboratory results:
   • Platelets

     Dose Escalation Phase: Platelets >10 x 10⁹/L for ≥7 days without transfusions or growth factor support

     Cohort Expansion Phase: Platelets ≥10 x 10⁹/L

   • Serum creatinine ≤1.5 x upper limit of normal (ULN) or glomerular filtration rate (GFR) ≥60 mL/min
   • Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤2.5 x ULN (unless there is documented disease involvement in the liver, in which case AST/ALT ≤5.0 x ULN)
   • White blood cell (WBC) blast count <20 x 10⁹/L
   • Total bilirubin normal (except for subjects with Gilbert's syndrome, who must have total bilirubin <3.0 mg/dL)
   • Hemoglobin (Hgb) ≥9 gm/dL
   • Prothrombin time/partial thromboplastin time (PT/PTT) ≤1.5 x ULN
6. QTc (Bazett's formula [QTcB]) interval ≤480 msec (Section 9.3, ECGs).
7. Nonhematologic toxicity from prior therapy must have declined to ≤Grade 2.
8. Hematologic toxicity from prior therapy must have stabilized for at least 2 weeks.
9. Subject has an estimated life expectancy that, in the judgment of the Investigator, will permit the subject to complete at least 9 weeks of treatment.

Exclusion Criteria

1. 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)
2. History of or current CNS disease that might put the subject at increased risk of bleeding (e.g., thrombotic, embolic, or hemorrhagic cerebrovascular accident; transient ischemic attack; or known aneurysm)
   • Subjects with a history of migraines or controlled seizure disorder are not excluded. Subjects with symptoms of CNS involvement (e.g., persistent headaches, confusion) must have documented absence of CNS disease by imaging scan within 4 weeks prior to screening.
3. Major surgical procedure within 4 weeks prior to screening
   • Minor procedures without complications such as placement of central venous catheters, peripherally inserted central catheter (PICC) lines, or biopsies are allowed.
4. Active infection requiring IV antibiotics, IV antifungals, or IV antivirals within 2 weeks prior to Cycle 1, Day 1
5. Use of hydroxyurea or plasmapheresis within 7 days of starting treatment with KB004 (AML subjects only are allowed hydroxyurea).
6. Ongoing surgical or wound healing complications
7. Active, clinically significant bleeding (e.g., hemoptysis, rectal bleeding, or ulcer disease) within 4 weeks prior to screening
8. Uncontrolled systemic hypertension (e.g., systolic blood pressure >160 mmHg, diastolic blood pressure >100 mmHg on medication)
9. Clinically significant intercurrent illness (e.g., uncontrolled systemic infection, uncontrolled disseminated intravascular coagulation [DIC], myocardial infarction, uncontrolled symptomatic coronary artery disease or congestive heart failure, need for hemodialysis, or psychiatric illness/social situations that would limit compliance with study requirements)
10. For subjects with MM: POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes)
11. Pregnant or breastfeeding women
12. Unable to understand or unwilling to provide written informed consent
13. Known history of prolonged bleeding times or platelet dysfunction