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

Washington University School of Medicine50 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Acute Myelogenous Leukemia

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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 Outcomes

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

Time frame: 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.

Time frame: 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.

Time frame: Through 90 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)

* 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.

Time frame: 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.

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: At 1 year post-tranplantation

Cumulative Incidence of Disease Relapse/Progression After Transplantation of Hematopoietic Cells Mobilized With BL-8040 (Arm 2 Recipients Only)

Time frame: 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.

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: At 3 years post-transplantation

Median Peripheral Blood CD34+ Cell Count (Arm 1 Donor Only)

Time frame: At 3-4 hours after BL-8040

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

Overview

Conditions

Interventions

Eligibility

Locations (3)

Outcomes

Primary Outcomes

Secondary Outcomes