A Phase III, Safety, Tolerability and Efficacy of Combination Treatment of BL-8040 and G-GSF as Compared to Placebo and G-CSF for the Mobilization of Hematopoietic Stem Cells for Autologous TransplantatIon in Subjects With MM (GENESIS)

• ClinicalTrials.gov Identifier: NCT03246529
• Recruitment Status: Active, not recruiting
• First Posted: August 11, 2017
• Results First Posted: November 7, 2023
• Last Update Posted: February 8, 2024
• Sponsor: BioLineRx, Ltd.
• Information provided by (Responsible Party): BioLineRx, Ltd.

Tracking Information

• First Submitted Date: August 2, 2017
• First Posted Date: August 11, 2017
• Results First Submitted Date: April 27, 2023
• Results First Posted Date: November 7, 2023
• Last Update Posted Date: February 8, 2024
• Actual Study Start Date: March 23, 2018
• Actual Primary Completion Date: December 22, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 4, 2023)

Percentage of Subjects Mobilizing ≥6 × 10^6 CD34+ Cells/kg With up to 2 Apheresis Sessions [ Time Frame: From first day of study treatment (G-CSF) until day of second apheresis which was planned to occur on Day 6 ]

Percentage of subjects mobilizing ≥6 × 10^6 CD34+ cells/kg with up to 2 apheresis sessions in preparation for autologous hematopoetic cell transplantation (auto-HCT) after treatment with G-CSF + single administration of BL-8040/placebo. Based on central laboratory data.

Original Primary Outcome Measures (submitted: August 7, 2017)

Proportion of subjects mobilizing ≥6.0 x 106 CD34+ cells/kg with up to 2 apheresis sessions [ Time Frame: 18 months ]

Proportion of subjects mobilizing ≥6.0 x 106 CD34+ cells/kg with up to 2 apheresis sessions in preparation for auto-HCT after treatment with G-CSF + single administration of BL-8040 or G-CSF + placebo.

Current Secondary Outcome Measures (submitted: September 4, 2023)

• Percentage of Subjects Mobilizing ≥2 × 10^6 CD34+ Cells/kg in 1 Apheresis Session [ Time Frame: From first day of study treatment (G-CSF) until day of first apheresis which was planned to occur on Day 5 ]
  Percentage of subjects mobilizing ≥2 × 10^6 CD34+ cells/kg in 1 apheresis session after treatment with G-CSF + single administration of BL-8040/ placebo.
• Percentage of Subjects Mobilizing ≥6 × 10^6 CD34+ Cells/kg in 1 Apheresis Session [ Time Frame: From first day of study treatment (G-CSF) until day of first apheresis which was planned to occur on Day 5 ]
  Percentage of subjects mobilizing ≥6 × 10^6 CD34+ cells/kg in 1 apheresis session after treatment with G-CSF + single administration of BL-8040/ placebo.
• Time to Neutrophil Engraftment, After Auto-HCT [ Time Frame: End of engraftment period, which was defined as 29 days post transplantation ]
  Time to neutrophil engraftment after auto-HCT, where engraftment was defined as absolute neutrophil count (ANC) ≥0.5 × 10^9/L for 3 days or ≥1.0 × 10^9/L for 1 day following the conditioning regimen associated nadir.
• Time to Platelet Engraftment, After Auto-HCT [ Time Frame: End of engraftment period, which was defined as 29 days post transplantation ]
  Time to platelet engraftment, after auto-HCT, where engraftment was defined as the first of 3 consecutive measurements of platelet count ≥20 × 10^9/L without platelet transfusion support for 7 days following the conditioning regimen associated nadir.
• Subjects With Graft Durability at 100 Days Post Transplant/ Early Termination [ Time Frame: Day 100 Post-Transplantation (± 7 days) ]
  Subjects achieving graft durability were defined as meeting the following 2 criteria:

  • Platelet count ≥50 × 10^9/L without transfusion for at least 2 weeks.
  • Hemoglobin level ≥10 g/dL with no erythropoietin support or transfusions for at least 1 month.

  This analysis was performed in part 2 of the study only.

Original Secondary Outcome Measures (submitted: August 7, 2017)

• Proportion of subjects who collect ≥2.0 x 106 CD34+ cells/kg in 1 apheresis session [ Time Frame: 18 months ]
  Proportion of subjects who collect ≥2.0 x 106 CD34+ cells/kg in 1 apheresis session after treatment with G-CSF + single administration of BL-8040 or G-CSF + placebo.
• Proportion of subjects who collect ≥6.0 x 106 CD34+ cells/kg in 1 apheresis session [ Time Frame: 18 months ]
  Proportion of subjects who collect ≥6.0 x 106 CD34+ cells/kg in 1 apheresis session after treatment with G-CSF + single administration of BL-8040 or G-CSF + placebo.
• Time to neutrophil engraftment, after autologous hematopoietic cell transplantation [ Time Frame: 18 months ]
  Time to neutrophil engraftment, after autologous hematopoietic cell transplantation, as defined as ANC ≥0.5 x 109/L for 3 days or ≥1.0 x 109/L for 1 day following the conditioning regimen associated nadir.
• Time to platelet engraftment, after autologous hematopoietic cell transplantation [ Time Frame: 18 months ]
  Time to platelet engraftment, after autologous hematopoietic cell transplantation, as defined as the first of 3 consecutive measurements of platelet count ≥20 x 109/L without platelet transfusion support for 7 days following the conditioning regimen associated nadir.
• Graft durability at 100 days post engraftment. [ Time Frame: 18 months ]
  Graft durability at 100 days post engraftment, after autologous hematopoietic cell transplantation.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase III, Safety, Tolerability and Efficacy of Combination Treatment of BL-8040 and G-GSF as Compared to Placebo and G-CSF for the Mobilization of Hematopoietic Stem Cells for Autologous TransplantatIon in Subjects With MM
• Official Title: A Phase III, Randomized, Placebo-Controlled, Multi-Centre Study Evaluating the Safety, Tolerability and Efficacy of Combination Treatment of BL-8040 and G-GSF 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
• Brief Summary: 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.

Detailed Description

• 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, PK and 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.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Subjects were randomized using a 2:1 ratio to receive G-CSF + BL-8040 or G-CSF + Placebo, respectively. Randomization will use permuted blocks stratifying subjects by US geographical region (NorthEast, SouthEast, MidWest, SouthWest and NorthWest), remission status (CR vs. PR), and baseline platelet count (< 200 × 10^9/L or ≥ 200 × 10^9/L).

Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment

• Condition: Multiple Myeloma

Intervention

• Drug: BL-8040 1.25 mg/kg + G-CSF
  Up to 2 SC injections of BL-8040 are anticipated during the study. Injections of G-CSF per standard of care
• Drug: Placebo +G-CSF
  Up to 2 SC injections of Placebo are anticipated during the study. Injections of G-CSF per standard of care

Study Arms

• Experimental: BL-8040 1.25 mg/kg + G-CSF
  Double-blind placebo-controlled setting designed to assess the safety, tolerability and efficacy of G-CSF + BL-8040 as compared to G-CSF + Placebo, for stem cell mobilization in MM.
  Intervention: Drug: BL-8040 1.25 mg/kg + G-CSF
• Active Comparator: Placebo + G-CSF
  Double-blind placebo-controlled setting designed to assess the safety, tolerability and efficacy of G-CSF + BL-8040 as compared to G-CSF + Placebo, for stem cell mobilization in MM.
  Intervention: Drug: Placebo +G-CSF

• Publications *: Crees ZD, Stockerl-Goldstein K, Vainstein A, Chen H, DiPersio JF. GENESIS: Phase III trial evaluating BL-8040 + G-CSF to mobilize hematopoietic cells for autologous transplant in myeloma. Future Oncol. 2019 Nov;15(31):3555-3563. doi: 10.2217/fon-2019-0380. Epub 2019 Sep 9.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 27, 2023): 180
• Original Estimated Enrollment (submitted: August 7, 2017): 207
• Estimated Study Completion Date: September 30, 2029
• Actual Primary Completion Date: December 22, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 109/L
      • Absolute neutrophil count more than 1.5 x 109/L

   2. Platelet count more than 100 x109/L Renal Function:

      • GFR value of ≥15 mL/min/1.732 calculated by MDRD equation

   3. Hepatic function:

      • ALT and/or AST ≤ 2.5 x ULN
      • Total Bilirubin ≤ 2.0 x ULN unless the subject has Gilbert disease

   4. Coagulation test:

      • INR or PT: ≤1.5xULN unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants
      • aPTT: ≤1.5xULN 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-HCT.
2. Failed previous 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. Pamolidomide: 7 days;
   5. Bortezomib: 7 days;
   6. Carfilzomib: 7 days;
   7. G-CSF: 14 days;
   8. 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 wiht 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 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, 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 NYHA Heart Failure >2.
21. ECG in screening showing QTcF > 470 msec, and/or PR > 280 msec,.
22. Mobitz II 2nd degree 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 notin 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 78 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany, Hungary, Italy, Spain, United States

Administrative Information

• NCT Number: NCT03246529
• Other Study ID Numbers: BL-8040.SCM.301
• 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

• Plan to Share IPD: No

• Current Responsible Party: BioLineRx, Ltd.
• Original Responsible Party: Same as current
• Current Study Sponsor: BioLineRx, Ltd.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: John DiPersio, MD; Washington University School of Medicine
• Principal Investigator: Crees Zachary, MD; Washington University School of Medicine

• PRS Account: BioLineRx, Ltd.
• Verification Date: February 2024