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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 : April 8, 2021
Sponsor:
Collaborator:
BioLineRx, Ltd.
Information provided by (Responsible Party):
Washington University School of Medicine

Tracking Information
First Submitted Date  ICMJE December 17, 2015
First Posted Date  ICMJE December 24, 2015
Results First Submitted Date  ICMJE April 9, 2019
Results First Posted Date  ICMJE May 1, 2019
Last Update Posted Date April 8, 2021
Actual Study Start Date  ICMJE March 31, 2016
Actual Primary Completion Date April 12, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 21, 2015)
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 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 3, 2020)
  • 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
  • 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.
  • 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.
  • 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 ]
  • 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 ]
  • Cumulative Incidence of Grade 2-4 Acute Graft Versus Host Disease (GvHD) as Measured by Minnesota Acute GVHD Criteria (Arm 2 Recipients Only) [ Time Frame: Day 100 ]
    • 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
    • The cumulative incidence of grade 2-4 acute GVHD was determined using competing risk analysis. Competing risks for acute GVHD were death, relapse, and graft failure.
  • Cumulative 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
    • The cumulative incidence of chronic GVHD was determined using competing risk analysis. Competing risks for acute GVHD were death, relapse, and graft failure.
  • 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 ]
  • 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
  • Cumulative 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
  • 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
  • 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.
  • 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
  • Median Peripheral Blood CD34+ Cell Count (Arm 1 Donor Only) [ Time Frame: At 3-4 hours after BL-8040 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 21, 2015)
  • Safety and Tolerability of BL-8040 in Healthy Donors as Measured by Number and Grade of Adverse Events (Arm 1 Donors Only) [ Time Frame: 5 years ]
    -Adverse events will be graded according to the NCI CTCAE version 4.03
  • Time to Neutrophil Engraftment Post-transplant in Patients Undergoing Allogeneic Stem Cell Transplant (Arm 2 Recipients Only) [ Time Frame: Up to Day 21 ]
    -Time to neutrophil engraftment is measured by determining the first of 3 consecutive measurements of neutrophil count ≥ 500/μL following conditioning regimen induced nadir.
  • Time to Platelet Engraftment Post-transplant in Patients Undergoing Allogeneic Stem Cell Transplant (Arm 2 Recipients Only) [ Time Frame: Up to 1 year after transplantation ]
    -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.
  • Incidence of primary graft failure after transplantation of hematopoietic cells mobilized with BL-8040 (Arm 2 Recipients only) [ Time Frame: Up to 1 year after transplantation ]
  • 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 ]
  • Incidence of grade 2-4 acute graft versus host disease (GvHD) in patients who have undergone transplantation of hematopoietic cells mobilized with BL-8040 (Arm 2 Recipients only) [ Time Frame: Up to 100 days after transplantation ]
    -Acute GVHD rate and severity for the first 100 days after PBSC infusion will be assessed based on modified Glucksberg criteria
  • Incidence of Chronic GvHD in Patients Who Have Undergone Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only) [ Time Frame: Up to 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
  • Proportion of Subjects 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 ]
  • 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
  • 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
  • Incidence of Disease Relapse/Progression After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only) [ Time Frame: Up to 1 year 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
  • Probability of Event Free Survival After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only) [ Time Frame: Up to 1 year 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.
  • Probability of Overall Survival After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only) [ Time Frame: Up to 1 year after transplantation ]
    -The time from Day 0 to death
  • Change in peripheral blood CD34+ cells concentration (Arm 1 Donor only) [ Time Frame: Up to Day 2 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of BL-8040 for the Mobilization of Donor Hematopoietic Stem Cells and Allogeneic Transplantation in Patients With Advanced Hematological Malignancies
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: BL-8040
  • Procedure: Leukapheresis
  • Procedure: Hematopoietic cell transplant
Study Arms  ICMJE
  • 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.
    Interventions:
    • 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
    Intervention: Procedure: Hematopoietic cell transplant
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 4, 2018)
50
Original Estimated Enrollment  ICMJE
 (submitted: December 21, 2015)
48
Estimated Study Completion Date  ICMJE April 12, 2023
Actual Primary Completion Date April 12, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02639559
Other Study ID Numbers  ICMJE 201602037
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Washington University School of Medicine
Study Sponsor  ICMJE Washington University School of Medicine
Collaborators  ICMJE BioLineRx, Ltd.
Investigators  ICMJE
Principal Investigator: Geoffrey Uy, M.D. Washington University School of Medicine
PRS Account Washington University School of Medicine
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP