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

• ClinicalTrials.gov Identifier: NCT01838395
• Recruitment Status: Completed
• First Posted: April 24, 2013
• Last Update Posted: June 15, 2016
• Sponsor: BioLineRx, Ltd.
• Information provided by (Responsible Party): BioLineRx, Ltd.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia	Drug: Ara-C; Drug: BL-8040	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: April 2013
• Actual Primary Completion Date: March 2016
• Actual Study Completion Date: June 2016

Arms and Interventions

Arm

Intervention/treatment

Experimental: BL-8040 + Ara-C; 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; IV; Other Name: cytarabine; Drug: BL-8040; SC; Other Name: BL8040

Outcome Measures

Primary Outcome Measures :

1. Safety and tolerability [ Time Frame: "participants will be followed for the duration of hospital stay and the follow up period, an expected average of 6 weeks. ]
   • 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.

Secondary Outcome Measures :

1. Clinical efficacy [ Time Frame: Final Bone Marrow evaluation -Between day 20 and day 44 ]
   The outcome will be measured by response rates as assessed at final Bone Marrow evaluation based on Cheson 2003 criteria.
2. Apoptotic effect [ Time Frame: Final evaluation- between day 20 and day 44 ]
   Change in leukemic cell apoptosis in Peripheral Blood and Bone Marrow.
3. Mobilization [ Time Frame: Final evaluation- between day 20 and day 44 ]
   Mobilization of AML blasts from the bone marrow to the peripheral blood (PB) by cell counting
4. Pharmacokinetic profile [ Time Frame: Day 0 to day 7 ]
   • 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

Other Outcome Measures:

1. Pharmacodynamic parameters [ Time Frame: After end of study- an expected average of 6 weeks. ]
   To assess additional pharmacodynamic parameters relevant to CXCR4 inhibition by CXCR4 receptor occupancy

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

   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.

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 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 ( 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.

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.

Contacts and Locations

Locations

United States, Florida

Mayo Clinic

Jacksonville, Florida, United States, 32224

United States, Maryland

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, United States, 21231

United States, Missouri

Washington University School of Medicine

St. Louis, Missouri, United States, 63110

United States, New York

Memorial Sloan-Kettering Cancer Center

New York, New York, United States, 10065

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

Israel

Rambam Medical Center

Haifa, Israel, 31096

Shaare Zedek Medical Center

Jerusalem, Israel, 91031

Meir Medical Center

Kfar Saba, Israel

Chaim Sheba Medical Center

Ramat Gan, Israel, 52621

Tel-Aviv Sourasky Medical Center

Tel Aviv, Israel, 64239

Sponsors and Collaborators

BioLineRx, Ltd.

Investigators

• Study Chair: Arnon Aharon, MD; BioLineRx, Ltd.

More Information

• Responsible Party: BioLineRx, Ltd.
• ClinicalTrials.gov Identifier: NCT01838395
• Other Study ID Numbers: BL-8040.01
• First Posted: April 24, 2013
• Last Update Posted: June 15, 2016
• Last Verified: June 2016

Keywords provided by BioLineRx, Ltd.:

AML; Acute Myeloid Leukemia; Relapsed Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms by Histologic Type; Neoplasms; Cytarabine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs