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

Multiple Myeloma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02639559
• Other study ID #: 201602037
• Status: Completed
• Phase: Phase 2
• Start date: March 31, 2016
• Est. completion date: April 7, 2023

Study information

• Verified date: October 2023
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: April 7, 2023
• Est. primary completion date: April 12, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Acute Myelogenous Leukemia
• Chronic Myelogenous Leukemia
• Hematologic Neoplasms
• Hodgkin Disease
• Hodgkin's Disease
• Hodgkins Disease
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Lymphoma
• Lymphoma, Non-Hodgkin
• Multiple Myeloma
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Myeloproliferative Disorders
• Myeloproliferative Neoplasm
• Non-Hodgkin Lymphoma
• Non-Hodgkin's Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• BL-8040

Procedure:
• Leukapheresis

• Hematopoietic cell transplant

Locations

Country	Name	City	State
United States	Northside Hospital Cancer Institute	Atlanta	Georgia
United States	Ohio State University	Columbus	Ohio
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Washington University School of Medicine	BioLineRx, Ltd.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)		Up to Day 2
Secondary	Safety and Tolerability of BL-8040 in Healthy Donors as Measured by Number and Grade of Adverse Events (Arm 1 Donors Only)	-Adverse events will be graded according to the NCI CTCAE version 4.03	Up to 5 years
Secondary	Time to Neutrophil Engraftment Post-transplant in Patients Undergoing Allogeneic Stem Cell Transplant (Arm 2 Recipients Only)	-Time to neutrophil engraftment is measured by determining the first of 3 consecutive measurements of neutrophil count = 500/µL following conditioning regimen induced nadir.	Up to Day 28
Secondary	Time to Platelet Engraftment Post-transplant in Patients Undergoing Allogeneic Stem Cell Transplant (Arm 2 Recipients Only)	-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.	Through 90 days
Secondary	Number of Recipients With Primary Graft Failure After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only)		Up to 1 year after transplantation
Secondary	Incidence of Secondary Graft Failure After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only)		Up to 1 year after transplantation
Secondary	Cumulative Incidence of Grade 2-4 Acute Graft Versus Host Disease (GvHD) as Measured by Minnesota Acute GVHD Criteria (Arm 2 Recipients Only)	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.	Day 100
Secondary	Cumulative Incidence of Chronic GvHD in Patients Who Have Undergone Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only)	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.	From Day 100 through 1 year after transplantation
Secondary	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)		Up to Day 2
Secondary	Incidence of CMV Reactivation After Transplantation of Hematopoietic Cells Mobilized With BL-8040 in CMV Seropositive Recipients	-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	Up to 1 year after transplantation
Secondary	Cumulative Incidence of Treatment-related Mortality After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only)	-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	Up to 1 year after transplantation
Secondary	Cumulative Incidence of Disease Relapse/Progression After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only)	-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	At 1 year post-tranplantation
Secondary	Cumulative Incidence of Disease Relapse/Progression After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only)	-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	At 2 years post-tranplantation
Secondary	Kaplan-Meier Estimate of Event Free Survival After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only)	-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.	At 2 years post-transplantation
Secondary	Kaplan-Meier Estimate of Event Free Survival After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only)	-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.	At 3 years post-transplantation
Secondary	Kaplan-Meier Estimate of Overall Survival After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only)	-The time from Day 0 to death	At 2 years post-transplantation
Secondary	Kaplan-Meier Estimate of Overall Survival After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only)	-The time from Day 0 to death	At 3 years post-transplantation
Secondary	Median Peripheral Blood CD34+ Cell Count (Arm 1 Donor Only)		At 3-4 hours after BL-8040

External Links

•   Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine