A Phase III, Safety, Tolerability and Efficacy of Combination Treatment of BL-8040 and Granulocyte Colony Stimulating Factor (G-CSF) as Compared to Placebo and G-CSF for the Mobilization of Hematopoietic Stem Cells for Autologous Transplantation in Subjects With Multiple Myeloma (MM)

A Phase III, Randomized, Placebo-Controlled, Multi-Centre Study Evaluating the Safety, Tolerability and Efficacy of Combination Treatment of BL-8040 and G-CSF as Compared to Placebo and G-CSF for the Mobilization of Hematopoietic Stem Cells for Autologous Transplantation in Subjects With Multiple Myeloma - The GENESIS Study

A total of 122 subjects were randomized into the study and investigated in the double-blind placebo-controlled setting to assess the efficacy and safety of G-CSF + BL-8040 as compared to G-CSF + placebo.

• Part 1: This lead-in period, designed to ascertain the dose of BL-8040, enrolled a total of 12 subjects to an open labeled treatment to assess the efficacy, safety, pharmacokinetic (PK) and pharmacodynamic (PD) parameters of treatment with G-CSF 10 µg/kg/day and BL-8040 1.25 mg/kg, per study protocol to goal collection of ≥ 6 × 10^6 CD34+ cells/kg.
• Part 2: Following the successful completion of Part 1, a total of 122 subjects were randomized into Part 2 of the study which employed a double-blind placebo-controlled setting to assess the efficacy and safety of G-CSF + BL-8040 as compared to G-CSF + placebo.

Inclusion Criteria:

1. Histologically confirmed Multiple Myeloma prior to enrolment and randomization.

2. At least 1 week (7 days) from last induction cycle of combination/multi-agent cyto-reductive chemotherapy (e.g., KRD [carfilzomib, lenalidomide, dexamethasone] or VRD (e.g., bortezomib, lenalidomide, dexamethasone) or last single agent chemotherapy (e.g., lenalidomide, pomalidomide, bortezomib, dexamethasone, etc.) prior to the first dose of G-CSF for mobilization.

3. Eligible for autologous hematopoietic stem cell transplantation according to the Investigator's discretion.

4. The subjects should be in first or second CR (including CR and SCR) or PR (including PR and VGPR).

5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

6. Adequate organ function at screening as defined as below:

   1. Hematology:

      • White blood cell counts more than 2.5 x 10^9/L
      • Absolute neutrophil count more than 1.5 x 10^9/L

   2. Platelet count more than 100 x10^9/L Renal Function:

      • Glomerular Filtration Rate (GFR) value of ≥15 mL/min/1.732 calculated by Modification of Diet in Renal Disease (MDRD) equation

   3. Hepatic function:

      • Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x ULN
      • Total Bilirubin ≤ 2.0 x Upper Limit Normal (ULN) unless the subject has Gilbert disease

   4. Coagulation test:

      • International Normalized Ratio (INR) or Prothrombin Time (PT): ≤1.5 x ULN unless subject is receiving anticoagulant therapy, as long as PT or Partial Thromboplastin Time (PTT) is within therapeutic range of intended use of anticoagulants
      • Activated Partial Thromboplastin Time (aPTT): ≤1.5 x ULN unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants

7. Male subjects must agree to use an adequate method of contraception starting with the first day of G-CSF administration through 30 days after the last dose of study drug.

8. Patients must have a signed study informed consent prior to entering the study.

Exclusion Criteria:

1. Previous history of autologous or allogeneic-Hematopoietic Cell Transplantation (HCT).

2. Failed previous Hematopoietic Stem Cell (HSC) collections or collection attempts.

3. Taken any of the listed below concomitant medications, growth factors or stimulating agents within the designated washout period:

   1. Dexamethasone: 7 days;
   2. Thalidomide: 7 days;
   3. Lenalidomide: 7 days;
   4. Pomalidomide: 7 days;
   5. Bortezomib: 7 days;
   6. Carfilzomib: 7 days;
   7. G-CSF: 14 days;
   8. Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) or Neulasta®: 21 days;
   9. Erythropoietin or erythrocyte stimulating agents: 30 days;
   10. Eltrombopag, romiplostim or platelet stimulating agents: 30 days;
   11. Carmustine (BCNU): 42 days/6 weeks;
   12. Daratumumab: 28 days;
   13. Ixazomib: 7 days.

4. Received >6 cycles lifetime exposure to thalidomide or lenalidomide.

5. Received >8 cycles of alkylating agent combinations.

6. Received >6 cycles of melphalan.

7. Received prior treatment with radioimmunotherapy (e.g., radionuclides, holmium).

8. Received prior treatment with venetoclax.

9. Plans to receive maintenance treatment within 60 days post-engraftment (e.g., lenalidomide, bortezomib, pomalidomide, thalidomide, carfilzomib, etc.)

10. Has received a live vaccine within 30 days of the planned start of G-CSF administration. Seasonal flu vaccines that do not contain live virus are permitted.

11. Known active central nervous system (CNS) metastases or carcinomatous meningitis.

12. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to BL-8040, G-CSF, or other agents used in the study.

13. Has an active infection requiring systemic therapy or uncontrolled infection.

14. Has a known additional malignancy that is progressing or requires active treatment.

15. Has an underlying medical condition that would preclude study participation.

16. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.

17. O2 saturation < 92% (on room air).

18. Personal history or family history of Long QT Syndrome or Torsade de Pointes.

19. History of unexplained syncope, syncope from an uncorrected cardiac etiology, or family history of sudden cardiac death.

20. Myocardial infarction, coronary artery bypass grafting (CABG), coronary or cerebral artery stenting and /or angioplasty, stroke, cardiac surgery, or hospitalization for congestive heart failure within 3 months or greater than Angina Pectoris Class >2 or New York Heart Association (NYHA) Heart Failure >2.

21. ECG in screening showing QTcF > 470 msec, and/or PR > 280 msec,.

22. Mobitz II 2nd degree Atrioventricular (AV) Block, 2:1 AV Block, High Grade AV Block, or Complete Heart Block, unless the patient has an implanted pacemaker or implantable cardiac defibrillator (ICD) with backup pacing capabilities.

23. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

24. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

25. Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the screening visit through 30 days after the last dose of study drug.

26. Has a known history of HIV (HIV 1/2 antibodies)

27. Has known active Hepatitis B (e.g., Hepatitis B Surface Antigen [HBsAg] reactive) or Hepatitis C (e.g., Hepatitis C Virus [HCV] RNA [qualitative] is detected).

28. Untreated or unsuccessfully treated Hepatitis B or C.