Safety Study of a Chemokine Receptor (CXCR4) Antagonist in Multiple Myeloma Patients

This study has been completed.
Sponsor:
Information provided by:
Biokine Therapeutics Ltd
ClinicalTrials.gov Identifier:
NCT01010880
First received: November 9, 2009
Last updated: June 9, 2011
Last verified: June 2011
  Purpose

BKT-140 drug substance is a highly selective chemokine receptor (CXCR4) antagonist, which is developed by Biokine as a novel therapy for Multiple Myeloma (MM, a type of blood cancer). The unique combination of activities of BKT140, i.e., the induction of the exit of blood cells such as stem cells and mature cells from the bone marrow to the peripheral blood, coupled with specific induction of MM cell death by BKT-140, represents a novel therapeutic strategy against MM.


Condition Intervention Phase
Multiple Myeloma
Drug: BKT140
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/IIA, Non-Randomized, Open Label, Single Dose, Dose-Escalation, Safety Study of BKT140, a CXCR4 Antagonist in Patients With Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Biokine Therapeutics Ltd:

Primary Outcome Measures:
  • White blood cell (WBC) count [ Time Frame: 24 hour ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • CD34+ cells [ Time Frame: 24 hour ] [ Designated as safety issue: No ]

Estimated Enrollment: 16
Study Start Date: October 2008
Study Completion Date: July 2010
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: BKT140
    BKT-140 drug substance is a highly selective CXCR4 antagonist. BKT140 will be injected S.C once at dose of 0.03, 0.1, 0.3, 0.9 mg/kg
Detailed Description:

The chemokine CXCL12 (also called SDF-1 - stromal-derived-factor-1) and its receptor, CXCR4 ((CXC Chemokine Receptor 4), a molecule endowed with potent chemotactic activity for hematopoietic cells, together play a pivotal role in the trafficking of hematopoietic stem cells to the bone marrow 10,11. The CXCL12/CXCR4 axis is also critically involved in the retention of hematopoietic cells within the BM microenvironment. Following chemotherapy and irradiation, the CXCL12/CXCR4 axis delays the recovery of the BM progenitor cells and the exit of mature cells such as neutrophils and monocytes to the periphery. Consequently, disruption of the CXCL12/CXCR4 interaction results in mobilization of hematopoietic cells including stem cells and a faster recovery of the treated BM.

BKT140 (4F-benzoyl-TN14003) is a highly selective and unique CXCR4 antagonist. Pre-clinical studies showed that BKT140 binds CXCR4 with high affinity (1nM) 13. Biokine has demonstrated the ability of the CXCR4 antagonist, BKT140, to mobilize various WBC such as neutrophils and monocytes as well as progenitor and stem cells, from the BM. The ability of BKT140 to stimulate the mobilization of these cells is superior to that of AMD3100, a CXCR4 antagonist that is in clinical development for mobilization of stem cells in MM and lymphoma patients, both qualitatively and quantitatively. BKT140 synergizes much more efficiently with G-CSF when compared to AMD3100. Moreover, Biokine has shown that BKT140, in synergism with G-CSF (NEUPOGEN®), is much more efficient in increasing the numbers of neutrophils and activated monocytes in the blood, by several folds as compared to G-CSF alone. BKT140 also shortens the neutropenic period due to an early release of neutrophils and monocytes from the BM. More importantly, BKT140, in synergism with G-CSF, reduces the anemic period caused by chemotherapy, due to a RBC production, which does not occur when G-CSF is given as a sole treatment. More importantly, BKT140, but not G-CSF or AMD3100, is also capable of shortening the period of cytopenia by boosting both the recovery of all hematopoietic cells in the BM and their exit to the periphery, and therefore shortening the period of cytopenia following chemotherapy or irradiation and BM transplantation. Importantly, Biokine has shown that upon interaction with CXCR4, BKT140, but not AMD3100, selectively, specifically and rapidly stimulates human leukemia and myeloma cell death in vitro and in vivo. Furthermore, BKT140 synergizes with other chemotherapeutic agents such as rapamycine to induce MM cell death.

  Eligibility

Ages Eligible for Study:   16 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males and females 18 to 65 years old inclusive
  • MM patients with clinically significant disease that achieved at least Partial Response (PR) after induction chemotherapy
  • Patients eligible for HDC with PBSC support.
  • Patients who require stem cell collection with CTX and G-CSF priming.
  • Normal LV functions (EF over 50%, DLCO over 50%)
  • Karnofsky score > 60%,
  • Patients must have normal renal and liver functions as defined below:

    • Total bilirubin ≤2.0 x institutional upper limit of normal (ULN), unless the patient has a known diagnosis of Gilbert's disease.
    • Aspartate transaminase (AST, SGOT) or alanine transaminase (ALT, SGPT) ≤3 x institutional ULN.
    • Serum creatinine ≤1.5 g/dL or calculated estimated creatinine clearance ≥40 mL/min
  • Polymorphonuclear neutrophil (PMN) count > 1,500
  • PLT >100,000
  • Hemoglobin > 9gr%
  • Women of child-bearing potential must have a negative serum or urine pregnancy test at enrollment.
  • If female, the patient is post-menopausal, surgically sterilized, or willing to use acceptable methods of birth control (e.g., hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide or abstinence) from the enrollment visit through 30 days after the administration of the study drug.
  • If male, the patient agrees to use an acceptable barrier method of contraception from the time of enrollment through 30 days after the administration of the study drug.
  • Prior to enrollment, the patient is capable of understanding the protocol and able to sign a written informed consent.

Exclusion Criteria:

  • Patients who have not achieved at least Partial Response (PR) following induction chemotherapy.
  • No pervious G-CSF therapy.
  • Creatinine clearance <40 mL /min.
  • Body temperature above 385 C on day 10.
  • Patients with blood pressure <105/60
  • Any of the following in the last 3 months prior to enrollment: Unstable Angina, Acute Myocardial Infarction (MI), Congestive Heart Failure, CVA, uncontrolled blood pressure
  • Pregnant or breast-feeding women.
  • Any medical condition which in the opinion of the Investigator places the patient at an unacceptably high risk for toxicities.
  • Treatment with any investigational agents in the last 21 days before study entry.
  • Any condition or circumstance which, in the opinion of the Investigator, would significantly interfere with the patient's protocol compliance and put the patient at increased risk.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01010880

Locations
Israel
Department of Hematology and Bone Marrow Transplantation,Rambam Medical Center
Haifa, Israel, 31096
Chaim Sheba Medical Center,Tel-Hashomer
Ramat Gan, Israel, 52621
Sponsors and Collaborators
Biokine Therapeutics Ltd
Investigators
Principal Investigator: Arnon Nagler, MD Chaim Sheba Medical Center
  More Information

Publications:
Responsible Party: Dr Orly Eizenberg, Biokine Therapeutics Ltd
ClinicalTrials.gov Identifier: NCT01010880     History of Changes
Other Study ID Numbers: BKTSC001
Study First Received: November 9, 2009
Last Updated: June 9, 2011
Health Authority: Israel: Ministry of Health

Keywords provided by Biokine Therapeutics Ltd:
Multiple Myeloma
CXCR4
Stem Cells
Mobilization
Transplantation
Chemotherapy

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on August 21, 2014