Phase IIa Study Evaluating Safety and Efficacy of BL-8040 in Relapsed/Refractory AML Patients

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if BL-8040 in combination with cytarabine (Ara-C) can help to control the disease in patients with Acute Myeloid Leukemia (AML) that has relapsed or did not respond adequately to previous treatment. The safety of the study drug combination will also be studied.

Detailed Description
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Open-label, multicenter, phase IIa, dose escalating study in subjects with relapsed/refractory AML, defined according to WHO criteria (1), including subjects who failed chemotherapy only and those who failed previous Autologous Stem Cell Transplantation (ASCT) / Allogeneic Stem Cell Transplantation (AlloSCT), provided at least 6 months have passed from transplant. Eligible subjects will receive subcutaneous (SC) injections of BL-8040 (monotherapy period) over two days (one injection per day) followed by concurrent administration of BL-8040 with standard salvage chemotherapy (combined period) over 5 days. During the combined period, BL-8040 will be administered 4 hours prior to chemotherapy. The chemotherapy will consist of cytarabine (Ara-C) 1.5 or 3 g/m2/d per dose (based on age), administered intravenously (IV) over 3 hours, for 5 days and will not be escalated. The first part of the study (Part 1) will include escalating dose groups and be considered the 'escalation phase'. Six potential dose levels (see Table 1) will be investigated starting at dose level 1. Patients will be accrued in a conventional 3+3 design. Applying this study design, the first cohort of 3 patients will be treated at dose level 1 and evaluated for dose escalation.

Official Title
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A PHASE IIA, MULTICENTER, OPEN-LABEL STUDY DESIGNED TO EVALUATE THE SAFETY AND EFFICACY OF ESCALATING DOSES OF BL-8040 IN ADULT SUBJECTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Ara-C
* Drug: BL-8040


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult men and women subjects aged 18 to 75, inclusive. Confirmed diagnosis of relapsed/refractory AML (WHO criteria) Refractory subjects, up to second consecutive salvage . Relapsed subjects including first and second relapse. AML relapse > 6 months since autologous or allogeneic stem cell transplantation, provided they are in first or second relapse and: No active graft-versus-host disease (GVHD > grade 1). No treatment with high dose steroids for GVHD (up to 20 mg Prednisolone or equivalent, Appendix G). No treatment with immunosuppressive drugs with the exception of low dose cyclosporine and tacrolimus (blood levels of 0.5-0.6 µg/mL). Clinical laboratory values should be as follows: WBC < 30,000/mL Blasts in PB ≤ 20,000. Treatment with Hydroxyurea is permitted up to 24 hrs prior to BL-8040 administration to achieve blast counts < 20,000 prior to enrollment. Creatinine < 1.3 mg/dL; if Creatinine is > 1 mg/dL the Creatinine clearance should be > 40 mL/min as calculated using the Cockcroft-Gault formula. Women of childbearing potential and all men must agree to use an approved form of contraception (e.g. oral, transdermal patch, implanted contraceptives, intrauterine device, diaphragm, condom, abstinence or surgical sterility) prior to study entry and for the duration of study participation through 30 days after the last dose of BL-8040. Confirmation that female subjects are not pregnant must be established by a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Subject is able and willing to comply with the requirements of the protocol. Subject is able to voluntarily provide written informed consent. Exclusion Criteria: Administration of conventional chemotherapy within 2 weeks of enrollment date. In the event that subjects have received chemotherapy > 2 weeks from the date of enrollment, they may be included provided they have recovered from the associated non-hematological toxicities to ≤ grade 1. Life expectancy of ≤ 2 months. Known allergy or hypersensitivity to any of the test compounds, materials or contraindication to test product. Use of investigational device or agents within 2 weeks of enrollment date. Low Performance Status (ECOG > 2; Appendix E). O2 saturation < 92% (on room air), evidence of TLS > grade 2 (according to the Cairo-Bishop criteria (3)) or leukostasis (2). Abnormal liver function tests: Serum aspartate transaminase (AST/SGOT) or alanine transaminase ( ALT/SGPT) 2 x upper limit of normal (ULN). Serum bilirubin. Total bilirubin > 2.0 mg/dL (34 µmol/L), conjugated bilirubin > 0.8 mg/dL. Left ventricular ejection fraction < 40 %. History of myocardial infarction or cerebrovascular accident within 6 months of enrollment date. Presence of active, uncontrolled infection. Known central nervous system disease (e.g., Alzheimer's disease). Acute promyelocytic leukemia. Exposure to high dose Ara-C within 6 months of enrollment. Subject has concurrent, uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place him/her at unacceptable risk, including, but not limited to: Subject has been diagnosed or treated for another malignancy within 3 years of enrolment, except in situ malignancy, or low-risk prostate, skin or cervix cancer after curative therapy A co-morbid condition which, in the view of the Investigators, renders the subject at high risk from treatment complications. Female subjects who are pregnant or breastfeeding. Prior clinically significant grade 3-4 non-hematological toxicity to high dose Ara-C or grade ≥ 2 of neurological toxicity. Seropositive for HIV antibodies (HIV1 and HIV2), Hepatitis C antibody (Hep C Ab) or a Hepatitis B carrier (positive for Hepatitis B surface antigen [HBsAg]). Unable to comply with study requirements in the opinion of the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BL-8040 + Ara-C<br>Eligible subjects will receive subcutaneous (SC) injections of BL-8040 (monotherapy period) over two days (one injection per day) followed by concurrent administration of BL-8040 with standard salvage chemotherapy (combined period) over 5 days. During the combined period, BL-8040 will be administered 4 hours prior to chemotherapy. The chemotherapy will consist of cytarabine (Ara-C) 1.5 or 3 g/m2/d per dose (based on age), administered intravenously (IV) over 3 hours, for 5 days and will not be escalated. | Drug: Ara-C<br>* IV<br>* Other names: cytarabine;Drug: BL-8040<br>* SC<br>* Other names: BL8040;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | General safety: Vital signs (oral temperature, blood pressure, pulse rate, respiratory rate and O2 saturation), 12-lead ECG and physical examination. Toxicity according to the latest version of NCI-CTCAE (currently V4.03, refer to ) for AEs and clinical laboratory profile as follows: Screening: record and report screening results, however not considered treatment emergent AEs. Throughout the study: record and report all AEs and SAEs according to GCP. | participants will be followed for the duration of hospital stay and the follow up period, an expected average of 6 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical efficacy | The outcome will be measured by response rates as assessed at final Bone Marrow evaluation based on Cheson 2003 criteria. | Final Bone Marrow evaluation -Between day 20 and day 44 | 
| Apoptotic effect | Change in leukemic cell apoptosis in Peripheral Blood and Bone Marrow. | Final evaluation- between day 20 and day 44 | 
| Mobilization | Mobilization of AML blasts from the bone marrow to the peripheral blood (PB) by cell counting | Final evaluation- between day 20 and day 44 | 
| Pharmacokinetic profile | Cmax - maximum BL-8040 plasma concentration Tmax - time to reach the maximum BL-8040 plasma concentration AUC0-t - Area under the BL-8040 plasma concentration-time curve AUC0-∞ - Area under the BL-8040 plasma concentration-time curve λz - elimination rate constant, determined by linear regression t1/2 - terminal elimination half-life, defined as 0.693/λz | Day 0 to day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, Acute Myeloid Leukemia, Relapsed Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia