Study Evaluating Combination of Luspatercept in LR-MDS Without RS Having Failed or Being Ineligible to ESA

Sponsor

Groupe Francophone des Myelodysplasies (Other)

Overall Status

Recruiting

CT.gov ID

NCT05181735

Collaborator

Celgene (Industry)

150

Enrollment

Locations

Arms

66.1

Anticipated Duration (Months)

4.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Study of the combination of luspatercept in low-risk myelodysplastic syndrom (LR-MDS) without ring sideroblasts (RS) having failed or being ineligible to ESA

Condition or Disease	Intervention/Treatment	Phase
MDS Myelodysplastic Syndromes	Drug: Luspatercept Injection [Reblozyl] Drug: Eprex	Phase 1/Phase 2

Detailed Description

Part A of the trial=Dose-finding Study: Determination the optimal dose level in terms of both toxicity and efficacy for luspatercept + ESA

Part B : Determination of the superiority and efficacy of the association Luspatercept+ESA (erythroipoiesis Stimulating Agent) over luspatercept alone in patients with lower risk MDS who failed to achieve a response or who subsequently relapsed after ESA, wihtout disease progression

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Phase I/ II Multicenter Study Evaluating Combination of Luspatercept in LR-MDS Without RS Having Failed or Being Ineligible to ESA

Actual Study Start Date :

May 18, 2022

Anticipated Primary Completion Date :

May 19, 2027

Anticipated Study Completion Date :

Nov 19, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (Luspatercept alone) Patients will receive Luspatercept (at the selected dose according to part A) subcutaneously on day 1 of each 21 day cycle (every three weeks). Doses schedules Part A : Level 1 : 1.75mg/kg Level -1 : 1.33mg/kg Level -2 : 0.8mg/kg	Drug: Luspatercept Injection [Reblozyl] All patients will receive Luspatercept subcutaneously on day 1 of each 21 day cycle (every 3 weeks) at the selected dose according to part A : 1.75mg/kg or 1.33 mg/kg or 0.8 mg/kg Other Names: ACE-536
Experimental: Arm B (Luspatercept + EPREX) Patients will receive Luspatercept (at the selected dose according to part A) subcutaneously on day 1 of each 21 day cycle (every three weeks) AND Epoetin alfa: At the selected dose (in part A) per week, subcutaneously, every week Doses schedules Part A : Level -2 : Luspatercept 0.8 mg/kg + EPREX 30000 UI Level -1 : Luspatercept 1.33 mg/kg + EPREX 30000 UI Level 1 : Luspatercept 1.75mg/kg + EPREX 30000 UI Level 2 : Luspatercept 1.75mg/kg + EPREX 60000 UI	Drug: Luspatercept Injection [Reblozyl] All patients will receive Luspatercept subcutaneously on day 1 of each 21 day cycle (every 3 weeks) at the selected dose according to part A : 1.75mg/kg or 1.33 mg/kg or 0.8 mg/kg Other Names: ACE-536 Drug: Eprex Epoietin alfa will be adminstered as a subcutaneous injection at the selected dose according to part A : 30 000 UI/week or 60 000 UI/week, every week Other Names: Epoietin alfa

Arm

Intervention/Treatment

Experimental: Arm A (Luspatercept alone)

Patients will receive Luspatercept (at the selected dose according to part A) subcutaneously on day 1 of each 21 day cycle (every three weeks). Doses schedules Part A : Level 1 : 1.75mg/kg Level -1 : 1.33mg/kg Level -2 : 0.8mg/kg

Drug: Luspatercept Injection [Reblozyl]

All patients will receive Luspatercept subcutaneously on day 1 of each 21 day cycle (every 3 weeks) at the selected dose according to part A : 1.75mg/kg or 1.33 mg/kg or 0.8 mg/kg

Other Names:

ACE-536

Experimental: Arm B (Luspatercept + EPREX)

Patients will receive Luspatercept (at the selected dose according to part A) subcutaneously on day 1 of each 21 day cycle (every three weeks) AND Epoetin alfa: At the selected dose (in part A) per week, subcutaneously, every week Doses schedules Part A : Level -2 : Luspatercept 0.8 mg/kg + EPREX 30000 UI Level -1 : Luspatercept 1.33 mg/kg + EPREX 30000 UI Level 1 : Luspatercept 1.75mg/kg + EPREX 30000 UI Level 2 : Luspatercept 1.75mg/kg + EPREX 60000 UI

Drug: Luspatercept Injection [Reblozyl]

All patients will receive Luspatercept subcutaneously on day 1 of each 21 day cycle (every 3 weeks) at the selected dose according to part A : 1.75mg/kg or 1.33 mg/kg or 0.8 mg/kg

Other Names:

ACE-536

Drug: Eprex

Epoietin alfa will be adminstered as a subcutaneous injection at the selected dose according to part A : 30 000 UI/week or 60 000 UI/week, every week

Other Names:

Epoietin alfa

Outcome Measures

Primary Outcome Measures

Part A : Dose-finding study [Evaluation of Dose-limiting toxicity (DLT) at Day 21 of cycle 1 for non-hematological toxicity , up to day 42 for hematological toxicity]
To determine the optimal dose level in terms of both toxicity and efficacy for luspatercept + EPO
Part B : Benefit of the association over the monotherapy [At week 25]
To determine, at Week 25, the superiority and efficacy of luspatercept + ESA over luspatecept alone

Secondary Outcome Measures

Response rate [3 months]
To determine the response rate (complete response (CR) +Partial Response (PR) + stable disease with Hematological Improvment (HI) according to IWG 2006 criteria) in each arm
Response duration [24 months]
Duration of response ends with date loss of response, relapse or death whichever occurs first
Overall survival [30 months]
Overall survival time ends for patients who die during the follow up period with the date of death and for patients who do not die during the follow up period with the date when the patient was last seen to be alive

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must meet all of the following criteria to participate in the study:

Myelodysplastic syndrome according to current WHO classification
Age ≥ 18 years
Patients with lower risk MDS according to IPSS classification (LOW, INT-1) without RS who failed to achieved a response or who subsequently relapse after ESA (at least 60000 U EPO-a over at least 12weeks or equivalent), without disease progression (or ineligible to ESA defined by EPO > 500 UI/l)
Hemoglobin < 9 gr/dl or Transfusion dependant (at least 3 RBCs in 16 wk in at least 2 transfusion episodes)
Non del(5q) syndrome
Adequat renal function, defined by creatinine less than 1.5 times the upper limit of normal, creatinine clearance ≥ 40 mL/min (MDRD formula).
Adequat liver function, defined by total bilirubin and transaminases less than 1.5 times the upper limit of normal.
Patient is not known to be refractory to platelet transfusions.
Written informed consent.
Patient must understand and voluntarily sign consent form.
Patient must be able to adhere to the visit schedule as outlined in the study and follow protocol requirements.
ECOG performance status 0-2 at the time of screening.
A FCBP (female of childbearing potential) for this study was defined as a sexually mature woman who: (1) had not undergone a hysterectomy or bilateral oophorectomy; or (2) had not been naturally postmenopausal (amenorrhea following cancer therapy did not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). A FCBP participating in the study must:
Have had 2 negative pregnancy tests as verified by the investigator prior to starting IP (unless the screening pregnancy test was done within 72 hours of Cycle 1 Day 1). She must have had agreed to ongoing a monthly pregnancy testing during the course of the study and after EOT
If sexually active, agreed to have used, and been able to comply with, highly effective contraception** without interruption, 5 weeks prior to starting IP, during treatment with IP (including dose interruptions), and for 12 weeks after discontinuation of IP.
** Highly effective contraception was defined in this protocol as the following (information also appeared in the ICF): Hormonal contraception (eg, birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation (tying your tubes), or a partner with a vasectomy
Male subjects must: Have agreed to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (eg, polyurethane), during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions, and for at least 12 weeks following IP discontinuation, even if he had undergone a successful vasectomy

Exclusion Criteria:

A patient meeting any of the following criteria is not eligible to participate in the study:

Severe infection or any other uncontrolled severe condition.
Uncontrolled hypertension
Significant cardiac disease - NYHA Class III or IV or having suffered a myocardial infarction in the last 6 months.
del(5q) syndrome
Use of investigational agents within 30 days or any anticancer therapy (including IMiD) within 2 weeks before the study entry with the exception of hydroxyurea. The patient must have recovered at least a grade 1 from all acute toxicity from any previous therapy.
Use of EPO within 4 weeks before the study entry
Active cancer, or cancer during the year prior to trial entry other than basal cell carcinoma, or carcinoma in situ of the cervix or breast.
Patient already enrolled in another therapeutic trial of an investigational drug.
Known HIV infection or active hepatitis B or C.
Women who are or could become pregnant or who are currently breastfeeding.
Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form.
Patient eligible for allogeneic stem cell transplantation.
Known allergies to luspatercept or EPO or any of its excipients.
No affiliation to a health insurance system.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	CHU Amiens-Picardie	Amiens	France	80054
2	CHU Angers	Angers	France	49933
3	Centre Hospitalier Victor Dupouy	Argenteuil	France	95107
4	CH Henri Duffaut d'Avignon	Avignon	France	84000
5	Centre Hospitalier de la Côte Basque	Bayonne	France	64109
6	Hôpital Avicenne	Bobigny	France	93009
7	CHU de Caen Côte de Nacre	Caen	France	14033
8	CHU de Grenoble	Grenoble	France	38043
9	CH Le Mans	Le Mans	France	72037
10	Hôpital Saint Vincent de Paul	Lille	France	59020
11	CHRU de Limoges - Hôpital Dupuytren	Limoges	France	87042
12	Institut Paoli Calmettes	Marseille	France	13273
13	Centre Hospitalier de Mont de Marsan	Mont-de-Marsan	France	40000
14	CHU Nantes - Hôtel Dieu	Nantes	France	44093
15	CHU de Nice - Hôpital Archet 1	Nice	France	06202
16	CHU de Nîmes	Nîmes	France	30029
17	CHR d'Orléans	Orléans	France	45067
18	Hôpital Saint Louis	Paris	France	75010
19	Hôpital Cochin	Paris	France	75014
20	Hôpital Necker	Paris	France	75015
21	CHU de Bordeaux - Hôpital Haut-Lévêque	Pessac	France	33604
22	Centre Hospitalier Lyon Sud	Pierre-Bénite	France	69495
23	CHU de Poitiers	Poitiers	France	86021
24	Centre Hospitalier de Périgueux	Périgueux	France	24019
25	CHU de Rennes - Hôpital Pontchaillou	Rennes	France	35033
26	Centre Henri Becquerel	Rouen	France	76038
27	Institut de Cancérologie de La Loire	Saint-Priest-en-Jarez	France	42271
28	CHU Toulouse - IUCT Oncopole	Toulouse	France	31059
29	CHU de Tours - Hôpital Bretonneau	Tours	France	37000
30	CHRU Nancy - Hôpitaux de Brabois	Vandœuvre-lès-Nancy	France	54511
31	Hôpital Paul BROUSSE	Villejuif	France	94800