A randomized phase I/ II multicenter study evaluating combination of luspatercept in LR-MDS without RS having failed or being ineligible to ESA

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Groupe Francophone Des Myelodysplasies

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

18 May 2022 → ongoing

Decision date (initial)

2024-10-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

BMS

External identifiers

EU CT number

2024-515354-24-00

EudraCT number

2021-000596-37

ClinicalTrials.gov

NCT05181735

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

- Part A of the trial=Dose-finding Study:
To determine the optimal dose level in terms of both toxicity and efficacy for luspatercept + EPO in patients with lower risk MDS according to IPSS classification without RS who failed to achieve a response or who subsequently relapsed after EPO, without disease progression

- Part B of the trial=Benefit of the association over the monotherapy:
To determine, at Week 25, the superiority and efficacy (transfusion independence for TD dependent patients and hematological improvement for non-TD dependent patient (Platzbecker et al. Blood 2018) of luspatercept + EPO over luspatecept alone in patients with lower risk MDS according to IPSS classification without RS who failed to achieve a response or who subsequently relapsed after EPO, without disease progression.

Secondary objectives 7

1. To determine the response rate (CR+PR + stable disease with HI according to IWG 2006 criteria) in each arm
2. To determine the response duration, time to IPSS progression, and loss of RBC transfusion independence in responders
3. To determine the rate and interval to AML evolution
4. To determine overall survival
5. To identify prognostic and predictive factors of response, including IPSS-R, IPSS-karyotype and somatic mutations
6. Safety
7. We will use CTCAE version 5 for evaluation of non-hematological toxicities and all grade III to IV drug related non hematological adverse event will be considered as a dose limiting toxicity. For laboratory AE, DLT will be considered for any Grade III to IV drug related AE lasting more than 7 days. For hematological toxicities, DLT will be considered only if myelosuppression is prolonged lasting greater than 42 days and without evidence of disease progression (bone marrow and or peripheral blood) will be considered as a dose limiting toxicity.

Conditions and MedDRA coding

Low risk myelodysplastic syndrom without RS having failed or being ineligible to Erythroid Stimulating Agent

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Myelodysplastic syndrome according to current WHO classification
2. Age ≥ 18 years
3. 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)
4. Hemogobin < 9 gr/dl or Transfusion dependant (at least 3 RBCs in 16 wk in at least 2 transfusion episodes)
5. Non del(5q) syndrome
6. Adequat renal function, defined by creatinine less than 1.5 times the upper limit of normal, creatinine clearance ≥ 40 mL/min (MDRD formula)
7. Adequat liver function, defined by total bilirubin and transaminases less than 1.5 times the upper limit of normal
8. Patient is not known to be refractory to platelet transfusions
9. Written informed consent
10. Patient must understand and voluntarily sign consent form
11. Patient must be able to adhere to the visit schedule as outlined in the study and follow protocol requirements
12. ECOG performance status 0-2 at the time of screening
13. 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: a) 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 b) 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 14

1. Severe infection or any other uncontrolled severe condition
2. Uncontrolled hypertension
3. Significant cardiac disease - NYHA Class III or IV or having suffered a myocardial infarction in the last 6 months
4. del(5q) syndrome
5. 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.
6. Use of EPO within 4 weeks before the study entry
7. 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
8. Patient already enrolled in another therapeutic trial of an investigational drug
9. Known HIV infection or active hepatitis B or C
10. Women who are or could become pregnant or who are currently breastfeeding
11. Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form
12. Patient eligible for allogeneic stem cell transplantation
13. Known allergies to luspatercept or EPO or any of its excipients
14. No affiliation to a health insurance system

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part A : The dose finding study aims at determining the optimal dose (OD) that is both tolerable and has an indication of therapeutic benefit for those patients. It will use both toxicity and efficacy binary outcomes: Dose limiting toxicity (DLT), with an observation period up to day 42 of cycle 1 ; Efficacy: Treatment response will be defined at day 21 of cycle 1 by an increase in hemoglobin level of 1.5 g/dl or above.
2. Part B: Erythroide response (HI-E) according to IWG2018 criteria at week 25 following randomization

Secondary endpoints 3

1. Duration of response
2. Progression-free-survival
3. Overall survival

Investigational products

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

Test 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Groupe Francophone Des Myelodysplasies

Sponsor organisation

Groupe Francophone Des Myelodysplasies

Address

Opital St Louis Hemato Seniors T4, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris

Postcode

75010

Country

France

Scientific contact point

Organisation

Groupe Francophone Des Myelodysplasies

Contact name

Lionel ADES

Public contact point

Organisation

Groupe Francophone Des Myelodysplasies

Contact name

Lionel ADES

Locations

2 EU/EEA countries · 41 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 21 files

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

Application history

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