Safety and efficacy of BL-8040 with G-CSF compared to Placebo with G-CSF for the collection of peripheral blood stem cells for autologous transplantation in patients with multiple myeloma

Start 17 May 2019 · Status Ongoing, recruitment ended · 4 EU/EEA countries · 8 sites · Protocol BL-8040.SCM.301

Overview

Sponsor-declared trial summary

Phase Therapeutic confirmatory (Phase III)

Status Ongoing, recruitment ended

Participants planned 122

Countries 4

Sites 8

Hematopoietic Stem Cell mobilization autologous transplantation in Multiple Myeloma

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 multiple myeloma (MM) subjects.

Key facts

Sponsor: Bioline Rx Ltd.
Participant type: Patients
Age range: 18-64 years, 65+ years
Gender: Male and Female
Therapeutic area: Diseases [C] - Neoplasms [C04]
Trial duration: 17 May 2019 → ongoing
Decision date (initial): 2024-07-22
Transition trial: Yes
Low-intervention: No
Rare-disease indication: Yes
Vulnerable population: Yes
Funding sources: BioLineRx Ltd.

External identifiers

EU CT number: 2024-511953-23-00
EudraCT number: 2018-001715-79
WHO UTN: U1111-1304-7744
ClinicalTrials.gov: NCT03246529

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Therapy, Efficacy, Safety, Pharmacoeconomic

Secondary objectives 5

- 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 multiple myeloma (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 multiple myeloma (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, 9 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.

Conditions and MedDRA coding

Hematopoietic Stem Cell mobilization autologous transplantation in Multiple Myeloma

Version	Level	Code	Term	System organ class
21.0	LLT	10028228	Multiple myeloma	10029104

Study design 2 periods

#	Title	Allocation	Blinding	Roles blinded	Arms
1	Part 1 An open label lead-in period (Part 1) was designed to ascertain the dose of BL-8040. A total of 12 subjects were enrolled to Part 1 to assess the efficacy, safety and tolerability of the treatment with G-CSF ~10 μg/kg/day (and maximum of 15 μg/kg) and BL-8040 1.25 mg/kg to achieve the goal collection of ≥6 x 10^6 CD34+ cells/kg. Following an independent DMC review of data for 11 subjects for safety and 10 subjects for efficacy, the DMC recommended to proceed to Part 2. All subjects treated during Part 1 continued to be followed up for 5 years or until early termination (whichever came first). This part has been completed in August 2023. Study Periods: Screening: Within 28 days prior to starting mobilization regimen (Day 1) Mobilization and Apheresis: From Day 1 to the day before myeloablative chemotherapy (Visit 9). Chemotherapy and Transplantation: From first day of myeloablation (Visit 9) to the first day of platelet and neutrophil engraftment (whichever comes later) after transplantation. Short-Term Graft Durability: From the first day after engraftment to Day 60 and 100 after transplantation. Long-Term Graft Durability: From 100 days after transplantation until 12 months after transplantation. Long-term Survival: Including OS, RFS and ARR from 12 months after transplantation.	Not Applicable	None
2	Part 2 Following the successful completion of Part 1, a total of 122 subjects was randomized into Part 2 of the study, which employed a randomized, double-blinded, placebo-controlled design to assess the efficacy, safety and tolerability of BL-8040 + G-CSF as compared to Placebo + G-CSF. Subjects were randomized in a 2:1 ratio to receive either BL-8040 or placebo, respectively, plus G-CSF. Randomization was stratified by remission status (Complete remission (CR) vs. Partial Remission (PR))a and baseline platelet count (<200 x 10^9/L or ≥200 x 10^9/L). Subjects underwent mobilization with G-CSF ~10 μg/kg (and maximum of 15 μg/kg) subcutaneously (SC) daily in the morning for up to 8 days. Beginning on the evening of Day 4, subjects received either a single injection of BL-8040 or placebo SC. In the morning of Day 5, a 5th dose of G-CSF was administered prior to apheresis. Subjects then underwent first apheresis per institutional protocol (4 blood volumes ±10% /apheresis). In the event that the subject did not reach the collection goal for mobilization (≥6.0 x 10^6 CD34+ cells/kg), on Day 6, a 6th dose of G-CSF was administered prior to the second apheresis session in an effort to reach a total of ≥6 x 10^6 CD34+ cells/kg. If the subject did not reach the collection goal for mobilization (≥6.0 x 10^6 CD34+ cells/kg), a second dose of BL-8040/placebo was administered in the evening of Day 6 and a 7th dose of G-CSF was administered in the morning of Day 7 prior to the third apheresis session. If the subject still did not reach the collection goal for mobilization (≥6.0 x 10^6 CD34+ cells/kg), a fourth and final apheresis was performed on Day 8 with an 8th dose of G-CSF administered prior to the apheresis, in an effort to collect a total of ≥6 x 10^6 CD34+ cells/kg, but at least ≥ 2 x 10^6 CD34+ cells/kg from the combined collections. Subjects who failed to collect the minimum required CD34+ cells/kg were subsequently managed per investigator preference in accordance with standard of care guidelines. They may have reattempted mobilization per standard of care after no less than 7 day “rest/wash-out” period (7 days from the last dose of BL-8040/placebo). Subjects who failed to collect enough CD34+ cells in four apheresis sessions were continued to be followed according to the protocol schedule of visits. Subjects randomized to Part 2 will continue to be followed until September 2028 (-30 days). By September 2028, the first randomized patient will complete approximately 8.5 years of follow-up and the last randomized patient will complete approximately 7 years of follow-up. Study Periods: Screening: Within 28 days prior to starting mobilization regimen (Day 1) Mobilization and Apheresis: From Day 1 to the day before myeloablative chemotherapy (Visit 9) Chemotherapy and Transplantation: From first day of myeloablation (Visit 9) to the first day of platelet and neutrophil engraftment (whichever comes later) after transplantation. Short-Term Graft Durability: From the first day after engraftment to Day 60 and 100 after transplantation. Long-Term Graft Durability: From 100 days after transplantation until 12 months after transplantation. Long-term Survival: Including OS, RFS and ARR from 12 months after transplantation; Until September 2028, for a maximal period of 8.5 years from randomization.	Randomised Controlled	Double	[{"id":172238,"code":2,"name":"Investigator"},{"id":172237,"code":3,"name":"Monitor"},{"id":172239,"code":1,"name":"Subject"}]	IMP: BL-8040: BL-8040 drug product was formulated as a sterile and non-pyrogenic lyophilized powder in a vial containing 73 mg BL-8040 free base peptide, on dry basis. BL-8040 was administered, as described in Part 2 Description, at a dose of 1.25 mg/kg by slow subcutaneous (SC) injection following reconstitution with 2 mL 0.45% sodium chloride for injection (half normal saline). IMP: Placebo: Placebo for BL-8040 drug product was formulated as a sterile and non-pyrogenic lyophilized powder in a vial containing 50 mg of mannitol. Placebo for BL-8040 was administered, as described in Part 2 Description, by slow subcutaneous (SC) injection following reconstitution with 2 mL 0.45% sodium chloride for injection (half normal saline).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

Patients must be between the ages of 18 and 78 years.
Patients must have a signed study informed consent prior to entering the study.
Histologically confirmed Multiple Myeloma prior to enrollment and randomization.
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.
Eligible for Autologous Hematopoietic stem cell transplantation according to the Investigator's discretion.
The subjects should be in first or second CR (including CR and SCR) or PR (including PR and VGPR).
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
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
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.
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.
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.

Exclusion criteria 28

Previous history of autologous or allogeneic-HCT.
Failed previous HSC collections or collection attempts.
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
Received >6 cycles lifetime exposure to thalidomide or lenalidomide.
Received >8 cycles of alkylating agent combinations
Received > 6 cycles of melphalan.
Received prior treatment with radioimmunotherapy, (e.g. radionuclides, holmium).
Received prior treatment with venetoclax
Plans to receive maintenance treatment within 60 days posttransplantation (e.g. lenalidomide, bortezomib, pomalidomide, thalidomide, carfilzomib, etc.).
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.
Known active CNS metastases or carcinomatous meningitis.
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.
Has an active infection requiring systemic therapy or uncontrolled infection.
Has a known additional malignancy that is progressing or requires active treatment.
Has an underlying medical condition that would preclude study participation.
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.
O2 saturation < 92% (on room air).
Personal history or family history of Long QT Syndrome or Torsade de Pointes
History of unexplained syncope, syncope from an uncorrected cardiac etiology, or family history of sudden cardiac death.
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.
ECG at screening showing QTcF > 470 msec and/or PR > 280 msec.
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.
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.
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
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.
Has a known history of HIV (HIV 1/2 antibodies).
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).
Untreated or unsuccessfully treated Hepatitis B or C.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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 G-CSF + single administration of BL-8040 or placebo.

Secondary endpoints 10

Efficacy Endpoint: Proportion of subjects who collect ≥2.0 x 10^6 CD34+ cells/kg in 1 apheresis session.
Efficacy Endpoint: Proportion of subjects who collect ≥6.0 x 10^6 CD34+ cells/kg in 1 apheresis session.
Additional Secondary Efficacy Endpoints: 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Motixafortide

PRD11183566 · Product

Active substance: Motixafortide
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SUBCUTANEOUS USE
Max daily dose: 1.25 mg/kg milligram(s)/kilogram
Max total dose: 2.5 mg/Kg milligram(s)/kilogram
Max treatment duration: 2 Day(s)
Authorisation status: Not Authorised
MA holder: BIOLINERX
Paediatric formulation: No
Orphan designation: Yes
Orphan designation number: EU/3/23/2885

Placebo 1

BL-8040 Placebo is formulated as a sterile and non-pyrogenic lyophilized powder in a vial containing 50 mg of mannitol. BL-8040 Placebo should be administrated SC following reconstitution with 2 mL 0.45% Sodium Chloride for Injection (Half Normal Saline).

N/A · Product

Other product name: N/A
Pharmaceutical form: N/A
ATC code: N/A — N/A
Marketing authorisation: N/A
MA holder: N/A
MA country: Iceland
Paediatric formulation: No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Bioline Rx Ltd.

Sponsor organisation: Bioline Rx Ltd.
Address: Modi’in Technology Park, 2 Hama'ayan 2 Hama'ayan
City: Modi'in Maccabim-Re'ut
Postcode: 7177871
Country: Israel

Scientific contact point

Organisation: Bioline Rx Ltd.
Contact name: Scientific and public contact point

Public contact point

Organisation: Bioline Rx Ltd.
Contact name: Scientific and public contact point

Third parties 16

Organisation	City, country	Duties
Neogenomics Laboratories Inc. ORG-100041804	Aliso Viejo, United States	Other, Laboratory analysis
Eurofins Pharma Bioanalytics Services US Inc. ORG-100049364	Saint Charles, United States	Other, Laboratory analysis
National Jewish Health ORG-100043431	Denver, United States	Other, Laboratory analysis
Medidata Solutions Inc. ORG-100016256	New York, United States	Interactive response technologies (IRT), E-data capture
Clario ORL-000006643	Philadelphia, United States	Other
Iqvia Rds Italy S.r.l. ORG-100038785	Milan, Italy	Code 12
Bioforum Ltd. ORL-000008243	Ness Ziona, Israel	Other, Data management
IQVIA RDS Spain S.L. ORG-100014508	Madrid, Spain	Code 12
Eurofins Lancaster Laboratories Inc. ORG-100012014	Lancaster, United States	Other, Laboratory analysis
FGK Clinical Research Kft. ORG-100051091	Budapest II, Hungary	Code 12
EVERSANA Life Science Services LLC ORL-000008240	Overland Park, United States	Code 8
Allucent (DE) GmbH ORG-100008157	Cologne, Germany	On site monitoring, Code 2
FGK Clinical Research GmbH ORG-100008669	Munich, Germany	Code 12
Q2 Solutions Ltd. ORL-000008242	Livingston, United Kingdom	Other, Laboratory analysis
Labcorp Early Development Laboratories Inc. ORG-100012865	Madison, United States	Other, Laboratory analysis
StatExcellence ORL-000008239	Kyriat Mozkin, Israel	Code 10

Locations

4 EU/EEA countries · 8 investigational sites

By country

Country	MS status	Planned subjects	Sites
Germany	Ongoing, recruitment ended	3	1
Hungary	Ongoing, recruitment ended	16	2
Italy	Ongoing, recruitment ended	17	2
Spain	Ongoing, recruitment ended	8	3
Rest of world United States	—	78	—

Investigational sites

Germany

1 site · Ongoing, recruitment ended

University Hospital Cologne AöR

Klinik I für Innere Medizin, Kerpener Strasse 62, Lindenthal, Cologne

Hungary

2 sites · Ongoing, recruitment ended

University Of Debrecen

Department of Haematology, Nagyerdei Korut 98, 4032, Debrecen

Del-Pesti Centrumkorhaz Orszagos Hematologiai Es Infektologiai Intezet

Hematológiai és Őssejt- transzplantációs Osztály, Albert Florian Ut 5-7, 1097, Budapest IX

Italy

2 sites · Ongoing, recruitment ended

Grande Ospedale Metropolitano Bianchi Melacrino Morelli

Hematology and Stem Cell Transplant Unit, Viale Europa, 89133, Reggio Calabria

Azienda Ospedaliero Universitaria Policlinico G Rodolico San Marco Di Catania

Divisione Di Ematologia, Via Santa Sofia 78, 95123, Catania

Spain

3 sites · Ongoing, recruitment ended

Hospital Universitario Ramon Y Cajal

Hematology Department, Carretera Del Colmenar Viejo Km 9 100, Por El Pardo, Madrid

Hospital Universitario 12 De Octubre

Hematology Department, Bloque D, Avenida De Cordoba Sn, Madrid

Hospital De La Santa Creu I Sant Pau

Hematology Department, Carrer De San Quinti 89, 08041, Barcelona

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Country	Trial start	Recruitment start	Recruitment end
Germany	2019-12-03	2020-02-29	2020-11-02
Hungary	2019-08-05	2020-01-17	2020-11-02
Italy	2019-05-17	2019-08-02	2020-11-02
Spain	2019-10-28	2020-03-13	2020-11-02

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Type	Title	Version
Protocol (for publication)	D1_Protocol_2024-511953-23_Red_m	7.1
Protocol (for publication)	D4_Patient facing documents_Blank_m	n.a.
Recruitment arrangements (for publication)	K1_Recruitment arrangements_Blank_m	n.a.
Recruitment arrangements (for publication)	K1_Recruitment arrangements_Blank_m	n.a.
Recruitment arrangements (for publication)	K1_Recruitment arrangements_Blank_m	n.a.
Recruitment arrangements (for publication)	K1_Recruitment arrangements_Blank_m	n.a.
Subject information and informed consent form (for publication)	L1_ICF_HUN_m	3.0
Subject information and informed consent form (for publication)	L1_Letter to Participants_PI change_HUN	1.0
Subject information and informed consent form (for publication)	L1_SIS and ICF Supplemental ICF for Extended FU_DEU_m	2.0
Subject information and informed consent form (for publication)	L1_SIS and ICF_DEU_Red_m	6.0
Subject information and informed consent form (for publication)	L1_SIS and ICF_ESP_Red_m	3
Subject information and informed consent form (for publication)	L1_SIS and ICF_ITA_4041_Red_m	4.1
Subject information and informed consent form (for publication)	L1_SIS and ICF_ITA_4042_Red_m	4.0
Subject information and informed consent form (for publication)	L1_SIS and ICF_Pregnancy_DEU_Red_m	1.0
Subject information and informed consent form (for publication)	L1_SIS and ICF_Pregnancy_ESP_m	1.0
Subject information and informed consent form (for publication)	L1_SIS and ICF_Pregnancy_ITA_m	2.0
Subject information and informed consent form (for publication)	L1_SIS_HUN_Red_m	3.0
Subject information and informed consent form (for publication)	L1_Supplemental SIS and ICF Extended FU_ESP_m	1.1
Subject information and informed consent form (for publication)	L1_Supplemental SIS and ICF Extended FU_HUN_m	2.0
Subject information and informed consent form (for publication)	L1_Supplemental SIS and ICF Extended FU_ITA_m	1.0
Subject information and informed consent form (for publication)	L2_Patient Card_HUN	2.0
Subject information and informed consent form (for publication)	L3_Letter to Physicians_HUN	2.0
Synopsis of the protocol (for publication)	D1_Protocol Synopsis_2024-511953-23_Blank_m	n.a.

Application history

5 submissions — initial application plus substantial / non-substantial modifications

#	Type	Code	Submitted	Reference MS	Conclusion	Decision date
1	INITIAL	IN	2024-06-20	Spain	Acceptable with conditions 2024-07-18	2024-07-18
2	NON SUBSTANTIAL MODIFICATION	NSM-1	2024-10-17	Spain	Acceptable with conditions 2024-07-18	2024-10-17
3	SUBSTANTIAL MODIFICATION	SM-1	2024-12-18		Acceptable with conditions	2025-02-13
4	SUBSTANTIAL MODIFICATION	SM-2	2024-12-19		Acceptable with conditions	2025-01-10
5	SUBSTANTIAL MODIFICATION	SM-3	2026-03-02		Acceptable with conditions	2026-04-14