Multiple Myeloma resistant or refractory to Bortezomib and Lenalidomide and Pomalidomide MedDRA version: 18.0 Level: LLT Classification code 10028228 Term: Multiple myeloma System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Hu-Max-CD38
Product Name: Daratumumab
Product Code: JNJ-54767414
Pharmaceutical Form: Concentrate for solution for infusion
Sponsors
CHRU of Lille
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Must be able to understand and voluntarily sign an informed consent form 2. Must be able to adhere to the study visit schedule and other protocol requirements 3. Age ³ 18 years 4. Life expectancy > 6 months 5. Patients must have relapsed myeloma, and previously treated with Bortezomib, Lenalidomide, and Pomalidomide treatment, and being resistant or refractory to Bortezomib and Lenalidomide and Pomalidomide treatment. 6. Patients must have a clearly detectable and quantifiable monoclonal M-component value: ? IgG (serum M-component > 10g/l) ? IgA (serum M-component >5g/l) ? IgD (serum M-component > 0.5g/l) ? Light chain (serum M-component >1g/l or Bence Jones > 200mg/24H) ? In patients without measurable serum and urine M-protein levels when the absolute serum FreeLight chain (sFLC) is =100 mg/l and an abnormal sFLC K/? ratio (1.65) is found (Dispenzieri, 2008). 7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 8. Adequate bone marrow function within 5 days prior to 1st drug intake (cycle1, day 1, C1D1), without transfusion nor growth factor support within 5 days prior to 1st drug intake , defined as: ? Absolute neutrophils = 1000/mm3 ? Platelets = 50000/mm3 ? Haemoglobin = 8.5g/dl 9. Adequate organ function defined as: ? Serum creatinine clearance (Cockcroft-Gault formula) =30 ml/min ? Serum SGOT or SGPT < 3.0 X upper limit of normal (ULN) ? Serum total bilirubin < 2.0 mg/dL 10. Wash out period of at least 2 weeks from previous antitumor therapy or any investigational treatment or 5 half-lives from previous antibodies. 11. Women who are partners of men and of childbearing potential must be practicing one of the following methods of birth control: subcutaneous hormonal implant, levonorgestrel releasing intra-uterine system, medroxyprogesterone acetate depot, tubal sterilization, ovulation inhibitory progesterone only pills, or sexual intercourse with a vasectomized male partner (vasectomy must be confirmed by 2 negative semen analyses). Or women will commit to absolute and continuous abstinence confirmed to her physician on a monthly basis. Childbearing potential*. Contraception will start during therapy including dose interruptions, for 4 months after discontinuation of Daratumumab. *: Criteria for women of childbearing potential : This protocol defines a female of childbearing potential as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) 12. A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 28 days prior to dosing and the second within 48 hours prior to dosing, and remain on a highly effective method of birth control. The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception: • Highly effective methods: o Intrauterine device (IUD) o Hormonal (birth control pills, injections, implants) o Tubal ligation o Partner’s vasectomy • Additional effective methods: o
Exclusion criteria
Exclusion criteria: Patients meeting any of the following exclusion criteria are not eligible to enrol in this study: 1. Target disease exceptions: o Solitary bone/solitary extramedullary plasmocytoma o Patients with non-secretory MM and non-measurable MM o Evidence of central nervous system (CNS) involvement 2. Medical history and Concurrent disease: o Subjects with prior (= 5 years) or concurrent invasive malignancies except the following: ? Adequately treated basal cell or squamous cell skin cancer ? Incidental finding of low grade (Gleason 3+3 or less) prostate cancer ? Any cancer from which the subject has been disease free for at least 3 years. o Subject with known/underlying medical conditions that, in the investigator’s opinion would make the administration of the study drug hazardous (ie: uncontrolled diabetes or uncontrolled coronary artery disease) o Any uncontrolled or severe cardiovascular or pulmonary disease determined by the investigator including: ? NYHA functional classification III or IV congestive heart failure ? LVEF ( Left Ventricular Ejection Fraction) =45% ? Uncontrolled angina, hypertension or arrhythmia ? Myocardial infarction in the past 6 months o Subjects with grade 2 or greater peripheral neuropathy (as per NCI-CTCAEv4.0) o Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 4 months after the last dose of any component of the treatment regimen. Or, subject is a man who plans to father a child while enrolled in this study or within 4 months after the last dose of any component of the treatment regimen. o Known positive for HIV or active hepatitis B or C. o Subjects with psychiatric illnesses or social situations that would preclude them understanding the informed consent, study compliance or the ability to tolerate study procedures and/or study therapy o Subjects with known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) 3ULN 4. Prohibited prior therapies o Prior local irradiation within two weeks before first dose o Previous anti-CD38 therapy. 5. Allergies and Adverse Drug Reaction: o Hypersensitivity to Dexamethasone that would prohibit treatment with study therapy 6. Refusal to consent or protected by a legal regime (guardianship, trusteeship)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • To determine the best overall Response rate to Daratumumab plus Dexamethasone in myeloma patients resistant or refractory to Bortezomib and Lenalidomide and Pomalidomide • Determine the Overall Response Rate (ORR), including Partial Response (PR), Very Good Partial Response (VGPR), Complete Response (CR) to Daratumumab plus Dexamethasone in patients with RRMM resistant or refractory to Bortezomib and Lenalidomide, and Pomalidomide, using the International Myeloma Working Group (IMWG) response criteria. ;Secondary Objective: • To determine Safety of Daratumumab (type, frequency, severity, and relationship of adverse events to study treatment). Incidence of Treatment Emergent Adverse Event (TEAE), Serious Adverse Event (SAE) and laboratory abnormalities using National Cancer Institute (NCI) common toxicity criteria. • To determine VGPR and CR rate (IMWG criteria) • To determine the clinical benefit rate (CBR, Minor response (MR) or better). MR will be determined using the criteria of the European Organisation for Blood and Marrow Transplantation (EBMT) criteria. • To determine ORR including Partial Response (PR), Very Good Partial Response (VGPR), Complete Response (CR) and minor response (MR) to Daratumumab plus Dexamethasone at 3 months and 6 months of treatment. • To determine progression-free survival (PFS), • To determine time to progression (TTP). • To determine time to response (TTR) • To determine the Duration of Response (DOR) • To determine Overall Survival (OS) • ...;Primary end point(s): • The primary endpoint is the Overall Response Rate (ORR, PR or better) using the IMWG response criteria. ;Timepoint(s) of evaluation of this end point: Throughout the study using the IMWG response criteria. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Assess safety by type, frequency, severity, relationship of adverse events to study treatment and changes in vital signs, physical exams. Incidence of Treatment Emergent Adverse Event (TEAE), Serious Adverse Event (SAE) and laboratory abnormalities using National Cancer Institute (NCI) common toxicity criteria (CCTAE V4). • Response rate (VGPR and CR) to Daratumumab and Dexamethasone in the study population using IMWG response criteria. VGPR + CR rate and CR+- rate (complete response with normal FLC ratio) will also be determinate using IWMG criteria [1]. Determine the Clinical Benefit Rate (CBR = CR+ + CR + PR + MR), and duration of Clinical Benefit using EBMT criteria at 3 months and six months.. • Determine the OS (from the date of inclusion to last date of follow-up) of patients treated with Daratumumab+ Dexamethasone, Progression-free Survival (PFS), Event-free Survival (EFS) and time to progression (TTP). • Secondary efficacy variables for study treatment include: o Time to progression (TTP) obtained with study treatment versus the patient’s TTP(s) on prior therapies for MM o Duration of Response (DOR) • Assess QoL using EORTC QLQ30, MY20 and EQ5D-3L • Determine the Clinical Benefit Rate (CBR = CR+ + CR + PR + MR), and duration of CBR Determine the Disease Control Rate (DCR = CBR + stable disease [SD; for a minimum of 4 weeks]), as well as duration of DCR. • Compare PFS, ORR, DOR, DCR, and OS obtained with Daratumumab and Dexamethasone in patients with International Staging System (ISS) Stages II/III versus ISS Stage I Exploratory Endpoints • Compare response and survival with regards to chromosome copy numbers and chromosomal structural abnormalities present in tumour cells • Evaluation of ORR, DOR, PFS, and OS in patient with free light chain (FLC) MM treated with Daratumumab plus Dexamethasone • Correlational studies to evaluate response according to chromosome copy numbers and chromosomal structural abnormalitie | — |
Countries
Belgium, France
Contacts
Public ContactChanaz LOUNI / Ohyba BELLA (CRA)
Clinical reserach federation
Outcome results
None listed