Motixafortide and Natalizumab to Mobilize CD34+ Hematopoietic Stem Cells for Gene Therapies in Sickle Cell Disease (SCD)
Study Details
Study Description
Brief Summary
Hematopoietic stem cell (HSC)-based gene therapies now offer curative potential for patients with sickle cell disease (SCD), with decreased toxicity compared to allogeneic hematopoietic cell transplantation. However, effective HSC-based gene therapy depends on collecting sufficient HSCs to generate the therapeutic product, and currently available mobilization regimens carry unacceptable risk for patients with SCD or do not reliably yield optimal numbers of HSCs for gene therapy.
The investigators hypothesize that HSC mobilization with motixafortide (CXCR4i) alone and the combination of motixafortide plus natalizumab (VLA-4i) will be safe and tolerable in SCD patients. In addition, the investigators hypothesize that combined CXCR4 and VLA-4 blockade with motixafortide plus natalizumab will result in a rapid, robust, and synergistic increase in HSC mobilization to peripheral blood (PB) in patients with SCD, when compared to motixafortide alone.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Motixafortide followed by Motixafortide + Natalizumab Consenting and eligible patients will receive a single subcutaneous injection of motixafortide, followed by leukapheresis. Patient will then be followed for 6 weeks for adverse event monitoring. Following the 6-week monitoring period, patients will receive a single IV infusion natalizumab, then approximately 24 hours later, a single subcutaneous injection of motixafortide, followed by leukapheresis. Patients will then be followed for 6 weeks for adverse event monitoring. |
Drug: Motixafortide
Motixafortide is to be administered as a subcutaneous injection at a dose of 1.25 mg/kg
Other Names:
Drug: Natalizumab
Natalizumab will be administered as an IV infusion at a flat dose of 300 mg
Other Names:
Procedure: Leukapheresis
Leukapheresis consisting of a 1 Blood Volume (4-5L) procedure
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Outcome Measures
Primary Outcome Measures
- Safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs) [Through 28 days following administration of either motixafortide and/or natalizumab (estimated to be 8 weeks and 4 days)]
All toxicities will be graded using NCI-CTCAE Version 5.0 A DLT is an event occurring during the DLT period of 28 days following administration of either motixafortide and/or natalizumab that is considered to be at least possibly, probably or definitely related to study treatment by the investigator, and that meets the criteria below: Hematologic criteria Any Grade 5 serious adverse event Any Grade 4 serious adverse event, excluding Grade 4 hemolysis, bilirubin increase, leukocytosis, erythrocytosis, thrombocytosis, anemia, leukopenia, or febrile neutropenia Non-hematologic criteria Any Grade 4 or 5 serious adverse event. Any Grade 3 or higher arterial or venous thromboembolic event
Secondary Outcome Measures
- Number of CD34+ hematopoietic stem and progenitor cells (HSPCs) mobilized via leukapheresis per liter (L) of total volume (tV) processed following motixafortide alone and motixafortide + natalizumab [4-hours post motixafortide (Day 1) and 4-hours post motixafortide (approximately Day 44)]
The first blood draw will be on Day 1, 4 hours post-motixafortide treatment (immediately after the end of the first apheresis). The second blood draw will occur following the 6-week monitoring period, 4 hours post-motixafortide treatment (immediately after the end of the second apheresis).
- Number of CD34+ hematopoietic stem and progenitor cells (HSPCs) mobilized via leukapheresis per liter (L) of adjusted volume (aV) processed, following motixafortide alone and motixafortide + natalizumab [4-hours post motixafortide (Day 1) and 4-hours post motixafortide (approximately Day 44)]
The adjusted volume will be calculated as the total volume (tV) processed minus the volumes processed to establish/re-establish the HSC collection interface (iV) to yield an adjusted volume (aV) (i.e. tV-iV=aV). The number of apheresis alarms along with the amount of time, flow rate and volumes processed to establish the interface will be recorded during apheresis and entered into the eCRF. Use of aV will control for the effect of any apheresis alarms; which pause the centrifuge leading to loss of the collection interface. The first blood draw will be on Day 1, 4 hours post-motixafortide treatment (immediately after the end of the first apheresis). The second blood draw will occur following the 6-week monitoring period, 4 hours post-motixafortide treatment (immediately after the end of the second apheresis).
- Change in kinetics of CD34+ HSC mobilization in response to motixafortide alone and motixafortide + natalizumab in SCD patients, as assessed by CD34+ cells/ul in peripheral blood [From baseline through 4-hours post-last motixafortide treatment (estimated to be 44 days)]
Motixafortide alone (in 5 patients): Baseline #1, immediately pre-motixafortide; 2-hours post motixafortide; 4-hours post motixafortide Motixafortide + natalizumab (same 5 patients, 6 weeks later): Baseline #2, immediately pre natalizumab; 2-hours post natalizumab; 4-hours post natalizumab; 24-hours post natalizumab, immediately pre-motixafortide; 2-hours post motixafortide, 26-hours post natalizumab; 4-hours post motixafortide, 28 hours post natalizumab
- Incidence of adverse events related to motixafortide alone and motixafortide + natalizumab [From start of treatment through 6 weeks following completion of all treatment (estimated to be 3 months)]
-All toxicities will be graded using NCI-CTCAE Version 5.0
- Recommended phase II dose (RP2D) of motixafortide + natalizumab [Through 28 days following administration of study treatment for all patients enrolled (estimated to be 5 months)]
- Change in peak CD34+ HSC mobilization in response to motixafortide alone and motixafortide + natalizumab in SCD patients, as assessed by CD34+ cells/ul in peripheral blood [From baseline through 4-hours post-last motixafortide treatment (estimated to be 44 days)]
Motixafortide alone (in 5 patients): Baseline #1, immediately pre-motixafortide; 2-hours post motixafortide; 4-hours post motixafortide Motixafortide + natalizumab (same 5 patients, 6 weeks later): Baseline #2, immediately pre natalizumab; 2-hours post natalizumab; 4-hours post natalizumab; 24-hours post natalizumab, immediately pre-motixafortide; 2-hours post motixafortide, 26-hours post natalizumab; 4-hours post motixafortide, 28 hours post natalizumab
Eligibility Criteria
Criteria
Inclusion Criteria:
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Adult patients aged 18-40 years old
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Diagnosis of sickle cell disease (hemoglobin SS or Sβ0 genotype)
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Receiving automated RBC exchanges via apheresis-capable central venous access
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Able to hold hydroxyurea for at least 4 weeks prior to mobilization
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ECOG performance status ≤ 1
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Normal bone marrow and organ function as defined below:
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Leukocytes ≥ 2,000/mcL
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Absolute neutrophil count ≥ 1,500/mcl
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Platelets ≥ 75,000/mcl
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AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN at time of screening
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Creatinine clearance ≥ 30 mL/min by Cockcroft-Gault
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Baseline oxygen saturation ≥ 92% on room air
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Left ventricular ejection fraction (LVEF) ≥ 45% (Of note, transthoracic echocardiogram (TTE) will not be required for study. However, if the treating physician has clinical concerns for active cardiac disease for which a TTE is clinically warranted as standard of care, then an EF of ≥ 45% will be required).
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The effects of motixafortide and natalizumab on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation, and 3 months after completion of the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 3 months after completion of the study.
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Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
Exclusion Criteria:
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Patients may not have a history of receiving the following therapies: prior HCT or prior gene therapy
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Currently receiving concomitant immunosuppressants including 6-mercaptopurine, azathioprine, cyclosporine, methotrexate or concomitant inhibitors of TNF-α.
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Patient may not have a history of significant alloantibodies which, in the opinion of the treating physician and study investigator, significantly increase the risk of participation in this clinical trial.
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Currently receiving any other investigational agents.
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A history of progressive multifocal leukoencephalopathy
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A history of allergic reactions attributed to compounds of similar chemical or biologic composition to motixafortide or natalizumab.
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Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (including but not limited to HIV, active/untreated Hepatitis C and/or active/untreated Hepatitis B), ongoing/active vaso-occlusive pain crisis or uncontrolled SCD-related symptoms, symptomatic congestive heart failure, cerebrovascular accident, unstable angina pectoris, or cardiac arrhythmia.
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Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum/urine pregnancy test within 7 days of study entry and prior to each study agent administration/HSC mobilization.
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Determined by the investigator to be unable or unlikely to comply with the study procedures included in this protocol.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
Sponsors and Collaborators
- Washington University School of Medicine
- BioLineRx, Ltd.
Investigators
- Principal Investigator: Zachary Crees, M.D., Washington University School of Medicine
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- CREES