| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hematopoietic Stem Cell mobilization in Multiple Myeloma |
| Mobilisierung von blutbildenden Stammzellen bei multiplem Myelom |
|
| E.1.1.1 | Medical condition in easily understood language |
| Stem-cell collection for bone marrow transplant in subjects with cancer of blood cells |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the superiority of one dose of BL-8040 + G-CSF over placebo + G-CSF to mobilize ≥6.0 x 10^6 CD34+ cells/kg in up to 2 apheresis sessions in preparation for autologous hematopoietic cell transplantation (auto-HCT) in MM subjects. |
|
| E.2.2 | Secondary objectives of the trial |
- To demonstrate the superiority of one dose of BL-8040 + G-CSF over placebo + G-CSF to mobilize ≥2.0 x 10^6 CD34+ cells/kg in 1 apheresis session in preparation for autologous hematopoietic cell transplantation (auto-HCT) in MM subjects.
- To demonstrate the superiority of one dose of BL-8040 + G-CSF over placebo + G-CSF to mobilize ≥6.0 x 10^6 CD34+ cells/kg in 1 apheresis session in preparation for autologous hematopoietic cell transplantation (auto-HCT) in MM subjects.
- To descriptively assess the comparability between the effects of BL-8040 + G-CSF and placebo + G-CSF in time to neutrophil engraftment, platelet engraftment and the later of the two.
- To descriptively assess the comparability between the effects of BL-8040 + G-CSF and placebo + G-CSF on graft durability at 60 days, 100 days, and 6 and 12-months post-transplantation.
- To demonstrate that the use of (one or two doses) BL-8040 + G-CSF over placebo + G-CSF results in a reduction in resource use and cost savings. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must be between the ages of 18 and 78 years.
2. Patients must have a signed study informed consent prior to entering the study.
3. Histologically confirmed Multiple Myeloma prior to enrollment
4. At least one week (7 days) from last induction cycle of combination/multi-agent chemotherapy (e.g. KRD [carfilzomib, lenalidomide, dexamethasone] or VRD [bortezomib, lenalidomide, dexamethasone]) or from last single agent chemotherapy (e.g. lenalidomide, pomalidomide, bortezomib, dexamethasone, etc) prior to the first dose of G-CSF for mobilization.
5. Eligible for Autologous Hematopoietic stem cell transplantation according to the Investigator’s discretion.
6. The subjects should be in first or second CR (including CR and SCR) or PR (including PR and VGPR).
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
8. Adequate organ function at screening as defined below:
a. Hematology:
• White blood cell counts more than 2.5 x 10^9/L
• Absolute neutrophil count more than 1.5 x 10^9/L
• Platelet count more than 100 x10^9/L
b. Renal Function:
• GFR value of ≥15 mL/min/1.73^2 calculated by MDRD equation
c. Hepatic function:
• ALT and/or AST ≤ 2.5 x ULN
• Total Bilirubin ≤ 2.0 x ULN unless the subject has Gilbert disease
d. 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
9. Female subjects must be of non-childbearing potential or, if of childbearing potential, must have a negative serum pregnancy test at screening and negative urine/serum pregnancy test within 72 hours prior to G-CSF first administration.
10. Women of childbearing potential must agree to use 2 methods of effective contraception: One barrier method (e.g. diaphragm, or condom or sponge, each of which are to be combined with a spermicide) and one hormonal method, unless she uses a highly effective method. Highly effective methods of contraception include:
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal
• Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion
• Vasectomised partner
• Sexual abstinence
These methods must be used prior to study entry and for the duration of study participation through 30 days after the last dose of study treatment. Non-childbearing potential is defined as (by other than medical reasons):
• ≥45 years of age and has not had menses for over 2 years.
• Amenorrheic for > 2 years without a hysterectomy and oophorectomy and a Follicle Stimulating Hormone (FSH) value in the postmenopausal range upon pre-trial (screening) evaluation.
• Post hysterectomy, bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation at least 6 weeks prior to screening. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure; otherwise the subject must be willing to use two adequate barrier methods throughout the study, starting with the Screening Visit, through 30 days after the last dose of study drug. Information must be captured appropriately within the site's source documents.
11. 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. |
|
| E.4 | Principal 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:
a. Dexamethasone: 7 days
b. Thalidomide: 7 days
c. Lenalidomide: 7 days
d. Pamolidomide: 7 days
e. Bortezomib: 7 days
f. Carfilzomib: 7 days
g. G-CSF: 14 days
h. GM-CSF or Neulasta®: 21 days
i. Erythropoietin or erythrocyte stimulating agents: 30 days
j. Eltrombopag, romiplostim or platelet stimulating agents: 30 days
k. Carmustine (BCNU): 42 days/6 weeks
l. Daratumumab: 28 days
m. 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- transplantation (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 Class >2.
21. ECG at 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 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 breast feeding or expecting to conceive or women of childbearing potential unless consent to use two contraceptive methods or highly effective contraception as detailed above, 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
Proportion of subjects mobilizing ≥6.0 x 10^6 CD34+ cells/kg with up to 2 apheresis sessions in preparation for auto-HCT after single administration of BL-8040 + G-CSF or placebo + G-CSF. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
• Proportion of subjects who collect ≥2.0 x 10^6 CD34+ cells/kg in 1 apheresis session.
• Proportion of subjects who collect ≥6.0 x 10^6 CD34+ cells/kg in 1 apheresis session.
Additional Secondary Efficacy Endpoints:
The comparability between the effects of BL-8040 + G-CSF and placebo + G-CSF with the below endpoints will be assessed in a descriptive manner:
• Time from transplantation to neutrophil engraftment, defined as ANC ≥0.5 x 10^9/L for 3 consecutive days or ≥1.0 x 10^9/L for 1 day following the conditioning regimen associated nadir.
• Time from transplantation to platelet engraftment, defined as the first of 3 consecutive measurements of platelet count ≥20 x 10^9/L without platelet transfusion support for 7 days following the conditioning regimen associated nadir.
• Time from transplantation to engraftment, defined as the time to neutrophils and platelets engraftment, whichever comes later.
• Graft durability at 60 days post-transplantation.
• Graft durability at 100 days post-transplantation.
• Graft durability at 6 months post-transplantation.
• Graft durability at 9 months post-transplantation.
• Graft durability at 12 months post-transplantation. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United States |
| Germany |
| Hungary |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Part 1 of the study was completed in August 2023 collecting data of up to 5 years, while Part 2 of the study will continue until September 2028. (cf. Protocol Chapter 5.2.8.2 and Chapter 11.2). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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