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Safety and Efficacy of BL-8040 for the Mobilization of Donor Hematopoietic Stem Cells and Allogeneic Transplantation in Patients With Advanced Hematological Malignancies

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ClinicalTrials.gov Identifier: NCT02639559
Recruitment Status : Active, not recruiting
First Posted : December 24, 2015
Results First Posted : May 1, 2019
Last Update Posted : May 15, 2019
Sponsor:
Collaborator:
BioLineRx, Ltd.
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:

Current protocols use G-CSF to mobilize hematopoietic progenitor cells from matched sibling and volunteer unrelated donors. Unfortunately, this process requires four to six days of G-CSF injection and can be associated with side effects, most notably bone pain and rarely splenic rupture. BL-8040 is given as a single SC injection, and collection of cells occurs on the same day as BL-8040 administration. This study will evaluate the safety and efficacy of this novel agent for hematopoietic progenitor cell mobilization and allogeneic transplantation based on the following hypotheses:

  • Healthy HLA-matched donors receiving one injection of BL-8040 will mobilize sufficient CD34+ cells (at least 2.0 x 10^6 CD34+ cells/kg recipient weight) following no more than two leukapheresis collections to support a hematopoietic cell transplant.
  • The hematopoietic cells mobilized by SC BL-8040 will be functional and will result in prompt and durable hematopoietic engraftment following transplantation into HLA-identical siblings with advanced hematological malignancies using various non-myeloablative and myeloablative conditioning regimens and regimens for routine GVHD prophylaxis.
  • If these hypotheses 1 and 2 are confirmed after an interim safety analysis of the data, then the study will continue and include recruitment of haploidentical donors.

Condition or disease Intervention/treatment Phase
Acute Myelogenous Leukemia Acute Lymphoblastic Leukemia Chronic Myelogenous Leukemia Non-Hodgkin's Lymphoma Non-Hodgkin Lymphoma Hodgkin Disease Hodgkins Disease Hodgkin's Disease Multiple Myeloma Myelodysplastic Syndrome Myeloproliferative Neoplasm Drug: BL-8040 Procedure: Leukapheresis Procedure: Hematopoietic cell transplant Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study Evaluating the Safety and Efficacy of BL-8040 for the Mobilization of Donor Hematopoietic Stem Cells and Allogeneic Transplantation in Patients With Advanced Hematological Malignancies
Actual Study Start Date : March 31, 2016
Actual Primary Completion Date : April 12, 2018
Estimated Study Completion Date : April 12, 2023


Arm Intervention/treatment
Experimental: Arm 1: Donors
-Donors will receive subcutaneous (SC) BL-8040 in the morning (Day 1) followed by leukapheresis approximately 180 minutes (up to 270 minutes) after the injection per institutional protocol. If the donor does not reach the collection goal for mobilization (≥ 5.0 x 10^6 CD34+ cells/kg), a second leukapheresis will be performed on Day 2 (24 hours ± 2 hours from the BL-8040 injection) in an effort to reach a total of ≥ 5 x 10^6 CD34+ cells/kg and at least ≥ 2 x 10^6 CD34+ cells/kg from the combined collections.
Drug: BL-8040
Procedure: Leukapheresis
Experimental: Arm 2: Recipients
-All or part of the leukapheresis product will be infused into the recipient per institutional guidelines. The day of the infusion will be considered Day 0; if the infusion occurs over multiple days, the final day of infusion will be considered Day 0
Procedure: Hematopoietic cell transplant



Primary Outcome Measures :
  1. Number of Donors That Mobilize ≥ 2 x 10^6 CD34+ Cells/kg of Recipients Weight After a Single Injection of BL-8040 After no More Than Two Leukapheresis Collections (Arm 1 - Donors Only) [ Time Frame: Up to Day 2 ]

Secondary Outcome Measures :
  1. Safety and Tolerability of BL-8040 in Healthy Donors as Measured by Number and Grade of Adverse Events (Arm 1 Donors Only) [ Time Frame: Up to 5 years ]
    -Adverse events will be graded according to the NCI CTCAE version 4.03

  2. Time to Neutrophil Engraftment Post-transplant in Patients Undergoing Allogeneic Stem Cell Transplant (Arm 2 Recipients Only) [ Time Frame: Up to Day 28 ]
    -Time to neutrophil engraftment is measured by determining the first of 3 consecutive measurements of neutrophil count ≥ 500/μL following conditioning regimen induced nadir.

  3. Time to Platelet Engraftment Post-transplant in Patients Undergoing Allogeneic Stem Cell Transplant (Arm 2 Recipients Only) [ Time Frame: Through 90 days ]
    -Time to platelet engraftment is measured by determining the first of 3 consecutive measurements of platelet count ≥ 20,000/μL without platelet transfusion support for 7 days.

  4. Number of Recipients With Primary Graft Failure After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only) [ Time Frame: Up to 1 year after transplantation ]
  5. Incidence of Secondary Graft Failure After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only) [ Time Frame: Up to 1 year after transplantation ]
  6. Number of Participants Who Experienced Grade 2-4 Acute Graft Versus Host Disease (GvHD) as Measured by Minnesota Acute GVHD Criteria (Arm 2 Recipients Only) [ Time Frame: Up to 1 year after transplantation ]
    • Acute GVHD rate and worst severity is noted
    • 4 organ categories (skin, liver, lower GI, and upper GI)
    • Skin: Grade I: 1-2 , Grade II: 3, Grade III: N/A, Grade IV: 4
    • Liver: Grade I: 0, Grade II: 1, Grade III: 2-4, Grade IV: N/A
    • Lower GI: Grade I: 0, Grade II: 1: Grade II: 2-3: Grade IV: 4
    • Upper GI: Grade I: 0, Grade II: 1, Grade III: N/A, Grade IV: N/A

  7. Incidence of Chronic GvHD in Patients Who Have Undergone Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only) [ Time Frame: From Day 100 through 1 year after transplantation ]
    -Chronic GVHD rate and severity for the first 365 days after PBSC infusion will be assessed based on the NIH criteria

  8. Number of Participants Who Collect 5 x 106 CD34+ Cells/kg of Recipient Weight in a Single Leukapheresis and in 2 Leukapheresis Sessions (Arm 1 Donors Only) [ Time Frame: Up to Day 2 ]
  9. Incidence of CMV Reactivation After Transplantation of Hematopoietic Cells Mobilized With BL-8040 in CMV Seropositive Recipients [ Time Frame: Up to 1 year after transplantation ]
    -CMV reactivation will be defined as a positive test for CMV viremia as determined by an antigenemia assay or quantitative PCR that results in the administration of antiviral treatment directed against CMV

  10. Incidence of Treatment-related Mortality After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only) [ Time Frame: Up to 1 year after transplantation ]
    -Death that results from a transplant procedure related complication (e.g. infection, organ failure, hemorrhage, GVHD) rather than from relapse of the underlying disease or an unrelated cause

  11. Incidence of Disease Relapse/Progression After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only) [ Time Frame: Up to 3 years after transplantation ]
    -Disease relapse occurs in recipients who entered transplant in CR. Progression occurs in recipients with existent disease at transplant who meet criteria for progressive disease post-transplant. A recipient will be considered relapsed when there is a recurrence of the original malignant disease after transplantation. Date of relapse/progression is defined as the date at which the first observation of hematologic, radiographic, or cytogenetic changes which signify progression/relapse is made

  12. Probability of Event Free Survival After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only) [ Time Frame: Up to 3 years after transplantation ]
    -An event is defined as either graft failure, disease relapse as evidenced by hematologic, radiographic, or cytogenetic changes, or death. The event free survival is the time from Day 0 to occurrence of the first event.

  13. Probability of Overall Survival After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only) [ Time Frame: Up to 3 years after transplantation ]
    -The time from Day 0 to death

  14. Median Peripheral Blood CD34+ Cell Count (Arm 1 Donor Only) [ Time Frame: At 3-4 hours after BL-8040 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria (DONOR):

  • Age 18 to 70 years of age.
  • ECOG performance status of 0 or 1.
  • PART 1: Donor must be a 5/6 or 6/6 HLA-matched sibling willing to donate PBSC for transplant.
  • PART 2: Donor must be a 5/6 or 6/6 HLA-matched sibling or 3/6 or 4/6 HLA haploidentical donor willing to donate PBSC for transplant. Haploidentical donors will be allowed to participate upon investigator decision and based on the data reached from 5/6 or 6/6 HLA matched transplant done during Part 1 of the study.
  • Adequate organ function defined by:

    • serum creatinine within normal limits or a minimum creatinine clearance (CrCl) value of ≥ 60 ml/min calculated using the Modification of Diet in Renal Disease (MDRD) Study equation
    • AST, ALT and total bilirubin ≤ 2x institutional upper limit of normal.
  • Women of childbearing potential and men must agree to use adequate contraception with two different forms, including one barrier method, during participation in the study and for 2 weeks following dosing with BL-8040. Abstinence is acceptable if this is the established and preferred contraception for the subject.
  • Female subjects must have a negative urine or serum pregnancy test within 10 days prior to taking study medication if of childbearing potential or must be of non-childbearing potential. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the subject to be eligible. Non-childbearing potential is defined as:

    -≥ 45 years of age and has not had menses for > 2 years

  • Amenorrheic for > 2 years without a hysterectomy and oophorectomy and a FSH value in the postmenopausal range upon pretrial (screening) evaluation
  • Post-hysterectomy, oophorectomy, or tubal ligation.
  • Able and willing to comply with the requirements of the protocol.
  • Able to understand and willing to sign an IRB-approved written informed consent document.

Inclusion Criteria (RECIPIENT):

  • Age 18 to 75 years
  • ECOG performance status of 0-2 (inclusive)
  • One of the following diagnoses:

    • Acute myelogenous leukemia (AML) in 1st or subsequent remission
    • Acute lymphoblastic leukemia (ALL) in 1st or subsequent remission
    • Chronic myelogenous leukemia (CML) in chronic or accelerated phase
    • Non-Hodgkin lymphoma (NHL) or Hodgkin's disease (HD) in 2nd or greater complete remission, partial remission
    • Chronic lymphocytic leukemia (CLL)
    • Multiple myeloma (MM)
    • Myelodysplastic syndrome (MDS)
    • Myeloproliferative neoplasm (MPN) excluding primary or secondary myelofibrosis
  • Adequate organ function defined by:

    • a creatinine clearance (CrCl) value of ≥ 60 ml/min by MDRD study equation
    • AST, ALT and a total bilirubin ≤ 2x institutional upper limit of normal.
  • Adequate cardiac function with a left ventricular ejection fraction ≥ 40%.
  • Adequate pulmonary function defined as NO severe or symptomatic restrictive or obstructive lung disease, and formal pulmonary function testing showing an FEV1 ≥50% of predicted and a DLCO ≥ 40% of predicted, corrected for hemoglobin.
  • Female subjects must have a negative urine or serum pregnancy test if of childbearing potential or be of non-childbearing potential. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the subject to be eligible. Non-childbearing potential is defined as:

    *≥ 45 years of age and has not had menses for > 2 years

    • Amenorrheic for > 2 years without a hysterectomy and oophorectomy and a FSH value in the postmenopausal range upon pretrial (screening) evaluation
    • Post-hysterectomy, oophorectomy, or tubal ligation.
  • Able to understand and willing to sign an IRB-approved written informed consent document.

Exclusion Criteria (DONOR):

  • Received any investigational agent within 30 days and/or 5 half-lives (of the other investigational agent), whichever is longer, of receiving BL-8040.
  • Active HIV or hepatitis B or C infection
  • Pregnant or breastfeeding.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Known allergy or hypersensitivity to any of the test compounds, materials, or contraindication to test products.
  • Any malignancies in the 2 years prior to baseline, excluding: basal cell carcinoma, in situ malignancy, low-risk prostate cancer, cervix cancer after curative therapy.
  • A comorbid condition which, in the view of the investigators, renders the subject at high risk from treatment complications.

Exclusion Criteria (RECIPIENT):

  • Recipient must not have received any investigational drug within 30 days of starting conditioning treatment.
  • Pregnant or breastfeeding.
  • Active HIV or hepatitis B or C infection.
  • Any medical condition which, in the opinion of the clinical investigator, would interfere with the evaluation of the patient. Subjects with a clinically significant or unstable medical or surgical condition or any other condition that cannot be well-controlled by the allowed medications permitted in the study protocol that would preclude safe and complete study participation, as determined by medical history, physical examinations, ECG, laboratory tests, or chest-X-ray and according to the investigator's judgment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02639559


Locations
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United States, Georgia
Northside Hospital Cancer Institute
Atlanta, Georgia, United States, 30342
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Washington University School of Medicine
BioLineRx, Ltd.
Investigators
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Principal Investigator: Geoffrey Uy, M.D. Washington University School of Medicine
  Study Documents (Full-Text)

Documents provided by Washington University School of Medicine:

Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT02639559     History of Changes
Other Study ID Numbers: 201602037
First Posted: December 24, 2015    Key Record Dates
Results First Posted: May 1, 2019
Last Update Posted: May 15, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Multiple Myeloma
Lymphoma, Non-Hodgkin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Acute
Hodgkin Disease
Myelodysplastic Syndromes
Myeloproliferative Disorders
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bone Marrow Diseases
Leukemia, Lymphoid