Etude : 54767414MMY2065 / LYNX /



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Acronyme
Nom
Traitement
Type d'étude
MÀJ
Présentation de l'étude
Acronyme : 54767414MMY2065 / LYNX

Nom :

Traitement : Induction

Type d'étude : Hors ciblage moléculaire

Dernière MÀJ : 28/01/2020
Titre
Spécialité(s)
CIM10 - Localisation(s)
Informations principales
Titre : A Phase 2 Study of Daratumumab Subcutaneous (Dara-SC) Administration in Combination With Carfilzomib and Dexamethasone (DKd) Compared With Carfilzomib and Dexamethasone (Kd) in Participants With Multiple Myeloma Who Have Been Previously Treated With Daratumumab Intravenous (Dara-IV) to Evaluate Daratumumab Retreatment

Spécialité : Tissus lymphoïde, hématopoïétique et apparentés
Localisation : C90 - Myélome multiple et tumeurs malignes à plasmocytes
Schéma
Phase
Stade
Ligne(s)
Informations complémentaires
Schéma : The purpose of this study is to compare the efficacy (rate of very good partial response [VGPR] or better as best response as defined by the International Myeloma Working Group [IMWG] criteria) of daratumumab subcutaneous (Dara-SC) in combination with carfilzomib and dexamethasone (Kd) with the efficacy of Kd in participants with relapsed refractory multiple myeloma who were previously exposed to daratumumab intravenous (Dara-IV) to evaluate daratumumab retreatment.


Study arms:
- Active Comparator: Arm A: Carfilzomib+Dexamethasone (Kd)
Participants will receive: carfilzomib 20 milligram per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1 and then 70 mg/m^2 on Days 8 and 15 of Cycle 1 and thereafter on Days 1, 8, 15 of Cycle 2 onwards.
Participants will receive dexamethasone 20 mg on Cycle 1 Day 1, a second dose of 20 milligram (mg) will be given on Cycle 1 Day 2 and 40 mg IV or orally on Days 8, 15, 22 for Cycle 1. Patients will then receive dexamethasone 40mg on days 1, 8, 15 and 22 for cycles 2-9, then on Days 1, 8, 15 for Cycle 10 onwards, until death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study. The total duration of each cycle is 28 Days.

- Experimental: Arm B: Dara-SC in combination with Kd (DKd)
Participants will receive daratumumab subcutaneous (Dara-SC) 1800 mg by SC injection on Days 1, 8, 15, 22 for Cycle 1 and 2, Days 1 and 15 for Cycle 3-6, Day 1 for Cycle 7 onwards.
Participants will receive carfilzomib 20 mg/m^2 IV on Cycle 1 Day 1 and then 70 mg/m^2 on Day 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2.
Participants will receive dexamethasone 20 mg on Cycle 1 Day 1, a second dose of 20 milligram (mg) will be given on Cycle 1 Day 2 and 40 mg IV or orally on Days 8, 15, 22 for Cycle 1. Patients will then receive dexamethasone 40mg on days 1, 8, 15 and 22 for cycles 2-9, then on Days 1, 8, 15 for Cycle 10 onwards, until death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study. The total duration of each cycle is 28 Days.


Main objective of the trial:
The primary objective is to compare the efficacy (rate of very good partial response [VGPR] or better as best response as defined by the International Myeloma Working Group [IMWG] criteria) of Dara-SC in combination with Kd with the efficacy of Kd in participants with relapsed refractory multiple myeloma who were previously exposed to daratumumab intravenous (Dara-IV) to evaluate daratumumab retreatment.

Secondary objectives of the trial:
• To further characterize the efficacy (progression-free survival [PFS], overall survival [OS], overall response rate [ORR], rate of complete response[CR]/stringent complete response [sCR]) of Dara-SC in combination with Kd
• To evaluate the minimal residual disease (MRD) negativity rate and durability of MRD negativity status
• To characterize the safety of Dara-SC in combination with Kd
• To determine time to next treatment
• To evaluate the pharmacokinetics (PK)of Dara-SC
• To determine the immunogenicity of daratumumab recombinant human hyaluronidase PH20 (rHuPH20)

Phase : II

Stade : NA

Rechute, Réfractaire
Informations libres de droit
Critères d'inclusion
Critères de non-inclusion
Informations libres de droit
Critères d'inclusion et de non-inclusion
Critères d'inclusion : 1. At least 18 years of age.
2. Documented multiple myeloma as defined by the criteria below:
* Multiple myeloma diagnosis according to the International Myeloma Working Group (IMWG) diagnostic criteria.
* Measurable disease at screening as defined by any of the following: Serum M-protein level ≥1.0 g/dL in participants with immunoglobulin G (IgG) type, or serum M-protein level ≥0.5 g/dL in participants with non- IgG type, or urine M-protein level ≥200 mg/24 hours; or Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio.
3. Evidence of a response (partial response or better based on investigator’s determination of response by IMWG criteria) to daratumumab-containing IV therapy with response duration of at least 4 months.
4. Relapsed or refractory disease as defined below:
* Relapsed disease is defined as an initial response to previous treatment, followed by confirmed PD by IMWG criteria >60 days after cessation of treatment.
* Refractory disease is defined as <25% reduction in M-protein or confirmed PD by IMWG criteria during previous treatment or ≤60 days after cessation of treatment.
5. Received 1 or 2 prior line(s) of treatment of which one contained Dara-IV, and completed Dara-IV at least 3 months prior to randomization. A single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of corticosteroids (no more than the equivalent of dexamethasone 40 mg/day for 4 days) would not be considered prior lines of therapy.
6. ECOG Performance Status score of 0, 1, or 2.
7. Pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:
a) hemoglobin ≥8 g/dL (≥5mmol/L) (without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted);
b) absolute neutrophil count (ANC) ≥1.0 × 10^9/L (prior growth factor support is permitted but must be without support within the 7 days prior to the laboratory test);
c) platelet count ≥75 ×10^9/L for participants in whom <50% of bone marrow nucleated cells are plasma cells; otherwise platelet count of ≥50×10^9/L. Transfusions are not permitted within 7 days of testing to achieve this minimum platelet count.
d) aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN);
e) alanine aminotransferase (ALT) ≤2.5 × ULN;
f) total bilirubin ≤1.5 × ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤1.5× ULN is required);
g) estimated creatinine clearance (CrCl) ≥20mL/min per 1.73m^2. CrCl to be calculated using estimated glomerular filtration rate Modification of Diet in Renal Disease (MDRD) formula.
h) albumin-corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6mmol/L)
8. Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy.
9. Women of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to randomization.
10. Each participant must sign an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study. Participants must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF

Critères de non-inclusion : 1. Previous treatment with Dara-SC.
2. Previoustreatment with carfilzomib.
3. Previous treatment with daratumumab within the last 3 months prior to randomization.
4. Discontinuation of Dara-IV due to a daratumumab-related AE.
5. Allergies, hypersensitivity, or intolerance to daratumumab, hyaluronidase, mAbs, human proteins, or their excipients (refer to the IB), or known sensitivity to mammalian derived products. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
6. Contraindications to the use of any components of the backbone treatment regimens, per local prescribing information.
7. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before randomization (except for investigational anti-myeloma treatments, which cannot be taken within 2 weeks or 5PK half-lives of the treatment from the first dose of daratumumab, whichever is longer, before the date of randomization).
8. Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study intervention.
9. Plans to father a child while enrolled in this study or within 3 months after the last dose of study intervention.
10. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
11. Received anti-myeloma treatment within 2 weeks or 5 PK half-lives of the treatment from the first dose of daratumumab, whichever is longer, before the date of randomization. The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days) up to 21 days before treatment. A list of anti-myeloma treatments with the corresponding PK half-lives is provided in the Site Investigational Product Procedures Manual.
12. Received autologous stem cell transplant within 12 weeks before the date of randomization, or the participant has previously received allogeneic stem cell transplant (regardless of timing).
13. Plans to undergo a stem cell transplant prior to progression of disease on this study.
14. Focal radiation therapy within 14 days prior to randomization with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma. Radiotherapy within 14 days prior to randomization on measurable extramedullary plasmacytoma is not permitted even in the setting of palliation for symptomatic management.
15. Clinical signs of meningeal involvement of multiple myeloma.
16. Either of the following:
a) Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) is <50% of predicted normal. Note that FEV1 testing also is required for participants suspected of having COPD and participants must be excluded if FEV1 is <50% of predicted normal.
b) Known moderate or severe persistent asthma, or a history of asthma within the last 2 years, or currently has uncontrolled asthma of any classification. (Participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.)
17. Concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease, pulmonary hypertension) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study.
18. Uncontrolled hypertension, defined as an average systolic blood pressure >159mmHg or diastolic >99 mmHg despite optimal treatment (measured following European Society of Hypertension/European Society of Cardiology 2013 guidelines).
19. Gastrointestinal disease that may significantly alter the absorption of oral drugs.
20. Myelodysplastic syndrome, plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström's macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) or amyloidosis.
21. Not able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder) or the participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
22. Cirrhosis of the liver.
23. Intolerance to hydration due to preexisting pulmonary or cardiac impairment

For full exclusion criteria, refer page no: 35 to 38 of the protocol
NCT
Promoteur
Coordonnateur
Informations relatives au promoteur
NCT :
NCT03871829
Promoteur :
JANSSEN
Type de sponsor : Industriel
JANSSEN - JANSSEN
00000 HORS FRANCE

Coordonnateur :
Centre investigateur
Investigateur
TEC / ARC / IDE
État
MÀJ
Informations relatives aux investigateurs
Centre investigateur :
Centre Hospitalier Universitaire de Lille - 2 Avenue Oscar Lambret - 59000 LILLE

Investigateur :
Professeur Thierry FACON

TEC / ARC / IDE :
Secrétariat de recherche
fanny.miquel@
chru-lille.fr
03.20.44.57.13

Statut de l'essai : OUVERT

MAJ : 17/01/2020