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

A study is designed to assess if BL-8040 in combination with cytarabine (Ara-C) can help controlling the disease in patients with Acute Myeloid Leukemia (AML) that have relapsed or did not respond adequately to previous treatment. The safety of the study drug combination will also be studied.

Open-label, multicenter, Phase IIa, dose escalating study in subjects with relapsed/refractory AML, defined according to WHO criteria, 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 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.

At the discretion of the Sponsor, additional subjects may be enrolled into a selected dose group to confirm safety and efficacy for selected dose. the portion of this study is considered expansion phase.

Eligibility Criteria:
Inclusion Criteria:

1. Adult men and women subjects aged 18 to 75, inclusive.
2. Confirmed diagnosis of relapsed/refractory AML (WHO criteria) Refractory subjects, up to second consecutive salvage . Relapsed subjects including first and second relapse.
3. 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).
4. Clinical laboratory values should be as follows:

   White Blood Cells (WBC) \< 30,000/mL Blasts in Peripheral Blood (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.
5. 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.
6. Subject is able and willing to comply with the requirements of the protocol.
7. Subject is able to voluntarily provide written informed consent.

Exclusion Criteria:

1. 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.
2. Life expectancy of ≤ 2 months.
3. Known allergy or hypersensitivity to any of the test compounds, materials or contraindication to test product.
4. Use of investigational device or agents within 2 weeks of enrollment date.
5. Low Performance Status (ECOG \> 2; Appendix E).
6. O2 saturation \< 92% (on room air), evidence of Tumor Lysis Syndrome (TLS) \> grade 2 (according to the Cairo-Bishop criteria (3)) or leukostasis (2).
7. Abnormal liver function tests:

   Serum aspartate transaminase (AST/SGOT) or alanine transaminase ( Alanine Transaminase (ALT)/Serum Glutamic Pyruvic Transaminase (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.
8. Left ventricular ejection fraction \< 40 %.
9. History of myocardial infarction or cerebrovascular accident within 6 months of enrollment date.
10. Presence of active, uncontrolled infection.
11. Known central nervous system disease (e.g., Alzheimer's disease).
12. Acute promyelocytic leukemia.
13. Exposure to high dose Ara-C within 6 months of enrollment.
14. 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.
15. Female subjects who are pregnant or breastfeeding.
16. Prior clinically significant grade 3-4 non-hematological toxicity to high dose Ara-C or grade ≥ 2 of neurological toxicity.
17. Seropositive for HIV antibodies (HIV1 and HIV2), Hepatitis C antibody (Hep C Ab) or a Hepatitis B carrier (positive for Hepatitis B surface antigen \[HBsAg\]).
18. Unable to comply with study requirements in the opinion of the Investigator.