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Study of the Anti-EphA3 Monoclonal Antibody KB004 in Subjects with EphA3-Expressing Hematologic Malignancies
|Leukemia, Acute Myeloid (AML)
|Myelodysplastic Syndrome (MDS)
- 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.
- Cohort Expansion Phase: The primary objective is to characterize preliminary clinical activity based on the International Working Group (IWG) criteria specific to that hematologic malignancy. Patients must have EphA3+ disease as assessed by IHC.
- For the Dose Escalation Phase only, a secondary objective is to examine the clinical activity of KB004.
- For both phases, secondary objectives are to: Exploratory
- Examine the safety and tolerability profile of KB004
- Describe the PK profile of KB004
- Assess the immunogenicity profile of KB004
- An exploratory objective of the Drug Expansion Phase only is to 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 IHC.
- In addition, exploratory objectives of both study phases are to:
- 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; describe the PD effects of KB004 as assessed by IHC
- Explore correlative pharmacogenomic (PG) information as it might relate to EphA3 expression and KB004 antitumor response
- Evaluate the impact of KB004 on the marrow microenvironment, including microvessel density
- Evaluate the downstream effect of KB004 on signal transduction
EphA3 expression as follows:
- Age ≥ 18 years
- 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. Once the Cohort Expansion Phase has started, subjects with AML will be 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 and subjects with MDS will no longer be eligible for inclusion in the Dose Escalation Phase.
- Cohort Expansion Phase
- Part A: AML or MDS, and EphA3 antigen expression as determined by IHC
- Part B: Other confirmed hematologic malignancy, and EphA3 antigen expression as determined by IHC
- 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 measurable soft tissue plasmacytoma > 2 cm, confirmed by either physical examination and/or applicable radiological evaluation (i.e., magnetic resonance imaging [MRI], computed tomography [CT], and/or bone marrow involvement > 30%)
- If MF is selected: Primary myelofibrosis (PMF), polycythemia myelofibrosis, post-polycythemia vera myelofibrosis (PPV MF), or post-essential thrombocythemia myelofibrosis (PET MF), confirmed according to the 2008 revised World Health Organization (WHO) criteria irrespective of JAK 2 mutation status
Eastern Cooperative Oncology Group (ECOG) (Appendix C) performance status ≤ 1 The following local laboratory results:
- 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).
- Dose Escalation Phase: Peripheral blood sample, bone marrow aspirate, and bone marrow biopsy obtained for measurement of EphA3 expression unless prior approval is obtained from KaloBios
- Cohort Expansion Phase: Bone marrow biopsy sample with ≥ 10% of nucleated cells that are EphA3+ by IHC. KaloBios may set an upper limit on EphA3 expression as additional data are accumulated.
QTc (Bazetts formula�QTcB) interval ≤ 480 msec (Section 9.3, ECGs) Nonhematologic toxicity from prior therapy must have declined to ≤ Grade 2 Hematologic toxicity from prior therapy must have stabilized for at least 2 weeks Subject has an estimated life expectancy, in the judgment of the Investigator, that will permit the subject to complete at least 9 weeks of treatment
- Platelets: Dose Escalation Phase: Platelets > 10 x 10^9/L for ≥ 7 days without transfusions or growth factor support. Cohort Expansion Phase: Platelets > 10 x 10^9/L.
- Serum creatinine ≤ 1.5 � upper limit of normal (ULN) or glomerular filtration rate (GFR) ≥ 60 mL/min
- Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 � ULN unless there is documented disease involvement in the liver, in which case AST/ALT ≤ 5.0 � ULN
- White blood cell (WBC) blast count <20 � 10^9/L total bilirubin normal (except for subjects with Gilberts syndrome, who must have total bilirubin < 3.0 mg/dL)
- Hemoglobin (Hgb) ≥ 9 gm/dL
- Prothrombin time/partial thromboplastin time (PT/PTT) ≤ 1.5 � ULN
- For previously treated AML subjects, length of first complete remission less than 3 months
- 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.
- POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes)
- 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.
- Use of hydroxyurea or plasmapheresis within 7 days of starting treatment with KB004
- Ongoing surgical or wound healing complications
- Active clinically significant bleeding (e.g., hemoptysis, rectal bleeding, or ulcer disease) within 4 weeks prior to screening
- Uncontrolled systemic hypertension (e.g., systolic blood pressure > 160 mmHg, diastolic blood pressure > 100 mmHg on medication)
- Clinically significant intercurrent illness (e.g., uncontrolled systemic infection, uncontrolled 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)
- Pregnant or breastfeeding women
- Unable to understand or unwilling to provide written informed consent
- Known history of prolonged bleeding times or platelet dysfunction
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