A Phase I/IIA, Non-Randomized, Open Label, Single Dose, Dose-Escalation, Safety Study of BKT140, a CXCR4 Antagonist in Patients With Multiple Myeloma
16 Years
65 Years
Both
Multiple Myeloma
Trial Information
A Phase I/IIA, Non-Randomized, Open Label, Single Dose, Dose-Escalation, Safety Study of BKT140, a CXCR4 Antagonist in Patients With Multiple Myeloma
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.
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.
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
White blood cell (WBC) count
Outcome Time Frame:
24 hour
Safety Issue:
No
Principal Investigator
Arnon Nagler, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Chaim Sheba Medical Center
Authority:
Israel: Ministry of Health
Study ID:
BKTSC001
NCT ID:
NCT01010880
Start Date:
October 2008
Completion Date:
July 2010
Related Keywords:
- Multiple Myeloma
- Multiple Myeloma
- CXCR4
- Stem Cells
- Mobilization
- Transplantation
- Chemotherapy
- Multiple Myeloma
- Neoplasms, Plasma Cell
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