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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Non-Hodgkin's Lymphoma, Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, Non-Hodgkin Lymphoma, Hodgkin Disease, Hodgkins Disease, Hodgkin's Disease, Multiple Myeloma, Myelodysplastic Syndrome, Myeloproliferative Neoplasm

Intervention / Treatment
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* Drug: BL-8040
* Procedure: Leukapheresis
* Procedure: Hematopoietic cell transplant


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Donors<br>-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<br> <br> Procedure: Leukapheresis<br> <br> |
| Experimental: Arm 2: Recipients<br>-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<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Incidence of Secondary Graft Failure After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only) |  | 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) | 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Median Peripheral Blood CD34+ Cell Count (Arm 1 Donor Only) |  | At 3-4 hours after BL-8040 |