Imatinib and BL-8040 (Novel Anti CXCR4 Antagonist) for Improving Molecular Response in Chronic Myelogenous Leukemia

Phase I/II Study Using Imatinib and s.c. BL-8040 (Novel Anti CXCR4 Antagonist) for Improving Molecular Response in Chronic Myelogenous Leukemia (CML) Patients in First Chronic Phase Achieving Less Than Optimal Response With Imatinib.

The aim of the study is to test the safety and efficacy of BL-8040 (a CXCR4 antagonist) in improving the response to imatinib in CML patients not achieving an optimal response with imatinib alone.

Study Overview

• Status: Withdrawn
• Conditions: Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: BL-8040

Detailed Description

To improve cytogenetic and molecular response of CML patients receiving Imatinib, who have not achieved an optimal response according to European LeukemiaNet (ELN) definitions , or MR4 after 24 months with Imatinib. This will be achieved by addition of the CXCR4 antagonist BL-8040, mobilizing CML leukemia stem cells from their protective bone marrow niche and exposing them to Imatinib and BL-8040-mediated apoptosis.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Israel
  • Tel-Hashomer, Israel, 52621
    • Chaim Sheba Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult men and women subjects aged 18 to 70, inclusive.
2. Confirmed diagnosis of chronic phase CML according to the WHO criteria (WHO 2008)

3. CML patients with sub-optimal response to Tyrosine Kinase Inhibitors, defined as "warning" in the ELN recommendations:

   Following 3 months: BCR-ABL1 > 10%, and/or Ph+ 36-95% Following 6 months: BCR-ABL1 1-10%, and/or Ph + 1-35% Following 12 months: BCR-ABL1 0.1-1 % Following 24 months: Less than MR4

4. Clinical laboratory values should be as follows:

   White blood cell count < 30 X 10*9/L Creatinine < 1.5 ULN

5. Women of childbearing potential and all men must agree to use approved form of contraception
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. CML patients not in chronic phase.
2. CML patients receiving Tyrosine Kinase Inhibitors other than Imatinib.
3. CML patients receiving Imatinib > 400 mg/day.
4. Patients not able to sign informed consent.
5. Known allergy or hypersensitivity to any of the test compounds or materials or contraindication to test product.
6. Low Performance Status (ECOG > 2).

7. Abnormal liver function tests:

   1. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) 2 x upper limit of normal (ULN).
   2. Serum bilirubin. Total bilirubin > 2.0 mg/dL (34 µmol/L), conjugated bilirubin > 0.8 mg/dL
8. Abnormal left ventricular ejection fraction, < 40 %.

9. Subject has concurrent, uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place him/her at unacceptable risk, including, but not limited to:

   1. 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
   2. A co-morbid condition which, in the view of the Investigators, renders the subject at high risk from treatment complications.
10. Women subjects who are pregnant or breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: BL-8040; Patients with chronic phase CML on Imatinib therapy (400 mg/day) achieving less than an optimal response will be treated with sc injections of BL-8040, while continuing Imatinib. The first part of the study will include escalating dose groups. Up to 4 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 (0.5 mg/kg) on Day 1, 15, 29 and 43. Patients will continue taking Imatinib 400 mg/day throughout the study. Dose escalation will continue until the maximal tolerated dose (MTD) is established and protocol specific stopping rules for toxicity are met. If no MTD is reached, dose escalation will continue up to dose level 4 (1.25 mg/kg).

Drug: BL-8040; BL-8040 will be added to imatinib to improve CML response.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the safety and tolerability of BL-8040 in combination with Imatinib in CML patients	The investigators will assess the safety of the BL-8040 by grading of toxicities according to standard Common Toxicity Criteria for Adverse Effects (CTCAE) criteria.	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the clinical efficacy of BL-8040 in combination with Imatinib	The cytogenetic and molecular response will be assessed by standard FISH and PCR test according to established criteria.	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess additional pharmacodynamic parameters relevant to CXCR4 inhibition	The investigators will test CXCR4 receptor occupancy and expression and additional pharmacodynamic endpoints relevant to CXCR4 inhibition.	2 months

Collaborators and Investigators

• Sponsor: Sheba Medical Center

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (Anticipated): November 1, 2016
• Study Completion (Anticipated): November 1, 2018

Study Registration Dates

• First Submitted: April 14, 2014
• First Submitted That Met QC Criteria: April 14, 2014
• First Posted (Estimate): April 16, 2014

Study Record Updates

• Last Update Posted (Estimate): August 15, 2016
• Last Update Submitted That Met QC Criteria: August 11, 2016
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: Chronic myeloid leukemia; imatinib; CXCR4 antagonist; BL-8040
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: SHEBA-13-0575-AN-CTIL