Patients with refractory or relapsed and refractory multiple myeloma MedDRA version: 20.0 Level: LLT Classification code 10028228 Term: Multiple myeloma System Organ Class: 100000004864
Conditions
Interventions
Trade Name: DARZALEX
Product Name: DARZALEX
Pharmaceutical Form: Infusion
INN or Proposed INN: DARATUMUMAB
CAS Number: 945721-28-8
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: e
Sponsors
Fundación PETHEMA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patient is, in the investigator’s opinion, willing and able to comply with the protocol requirements. 2. Patient has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care. 3. Patient must be at least 18 years of age. 4. Patient must have a confirmed diagnosis of symptomatic multiple myeloma and measurable secretory disease, defined as either serum monoclonal protein = 0,5 g/dL or urine monoclonal (light chain) protein = 200 mg/24 hours. For patients in whom measurable disease is performed by serum FLC, the involved FLC should be ? 10 mg/dL, with an abnormal serum FLC ratio. 5. Patients must have an ECOG performance status of 0, 1 or 2. 6. All patients must have received prior treatment with proteasome inhibitors and immunomodulators: A minimum of 2 consecutive cycles of proteasome inhibitors and immunomodulators are required. 7. Patients must have received = 3 prior lines of therapy and be refractory to the last line of therapy, or a. Be double refractory to proteasome inhibitors and immunomodulatory drugs on their most recent therapy, regardless of the prior number lines of therapy. b. Patients were thought to be refractory if they had progressed on or within 60 days of treatment with bortezomib and/or lenalidomide. 8. Patient has the following laboratory values within 14 days before Baseline visit (Day 1 of Cycle 1, before study drug administration): Platelet count = 75 x109/L, hemoglobin = 8.0g/dl and absolute neutrophil count (ANC) = 1.5 x 109/L; lower values may be accepted if clearly are due to bone marrow involvement by multiple myeloma (ANC = 1.0 x 109/L and platelets = 50 x109/L if bone marrow infiltration > 60%). Patients receiving hematopoietic growth factor support, including erythropoietin (EPO), darbepoetin, granulocyte-colony stimulating factor (G-CSF) may continue to do so. 9. Corrected serum calcium 20 mL/min as measured by 24-hour urine collection. 12. Women of childbearing potential must be practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: eg, established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; barrier methods: condom with spermicidal foam/gel/film/cream/suppository; male partner steritilization (the vasectomized partner should be the sole partner for that subject); true abstinence (when this is in line with the preferred and usual lifestyle of the subject) during and after the study (6 months after the last dose of any component of the treatment regimen). 13. A woman of childbearing potential must have a negative serum pregnancy test at screening within 10-14 days and 24 hours before commencing treatment. Females of reproductive potential must commit either to abstain continuously from heterosexual sexua
Exclusion criteria
Exclusion criteria: 1. Subject has received selinexor or daratumumab therapies previously. 2. Patients who are refractory to daratumumab or CD38 targeting antibody. 3. Subject has a diagnosis of plasma cell leukemia, primary amyloidosis, monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM). 4. Subject has previously received autologous stem cell transplantation within 12 weeks before Cycle Day 1, or has received other anti-myeloma treatment within 2 weeks before Cycle 1 Day 1 (with the exception of an emergency use of a short course [maximum 4 days] of corticosteroids). 5. Subject who had previously received allogeneic stem cell transplantation within the last year or even latter if they have evidence of graft versus host disease. 6. Subject has peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4. 7. Subject has had any prior or concurrent invasive malignancy (other than myeloma) within 5 years of study start except adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, localized prostate adenocarcinoma diagnosed = 3 years and without evidence of biochemical failure, or other cancer for which the subject has undergone potentially curative therapy and has no evidence of that disease for = 5 years. 8. Subject has had radiation therapy within 28 days of Cycle 1 Day 1. 9. Subject has meningeal involvement of multiple myeloma. 10. Subject has known severe chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second <60% of predicted normal), persistent asthma, or a history of severe asthma within 5 years. Subjects with known or suspected COPD or asthma must have a FEV test during screening. 11. Subjects have known moderate or severe persistent asthma within the past 2 years (see Appendix 8: National Heart, Lung, and Blood Institute (NHLBI) table of asthma severity), or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild ersistene asthma are allowed in the study). 12. Unstable cardiovascular function: a. Symptomatic ischemia, or b. Uncontrolled clinically-significant conduction abnormalities (e.g., patients with ventricular tachycardia on antiarrhythmics are excluded; patients with 1st degree atrioventricular (AV) block or asymptomatic left anterior fascicular block/right bundle branch block (LAFB/RBBB) will not be excluded), or c. Congestive heart failure (CHF) of New York Heart Association (NYHA) Class = 3, or d. Myocardial infarction (MI) within 3 months. 13. Patients with uncontrolled hypertension. 14. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose. 15. Subject is known to be seropositive for history of human immunodeficiency virus (HIV) or hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg] or antibodies to hepatitis B surface and core antigens [anti HBs and anti-HBc, respectively]) or hepatitis C (anti-HCV antibody positive or HCV-RNA quantitation positive). 16. Patients with any GI dysfunction who are unable to swallow tablets, or any GI dysfunction that could interfere with absorption of study treatment. 17. Serious psychiatric or medical conditions that, in the opinion of the investigator, could interfere
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary endpoint of the trial is to evaluate the efficacy of the combination selinexor, bortezomib plus low-dose dexamethasone and daratumumab in terms of overall response rate (ORR), including stringent complete responses, complete responses (CR), very good partial responses (VGPR), and partial responses (PR) according to the International Myeloma Working Group Criteria (IMWG). The clinical benefit rate (CR+VGPR+PR+MR) and disease control rate (CR+VGPR+PR+MR+SD) will be also evaluated.;Secondary Objective: - To evaluate the safety and tolerability of the combination, as determined by the incidence of clinical and laboratory toxicities. - To evaluate time-to-events data: time to progression, duration of response, progression free survival, and overall survival.;Primary end point(s): The primary statistical analysis of efficacy will be performed on ORR (achievement of CR or PR) for the overall ITT population and PP population, with supportive data provided by duration of response; The CBR and DCR will be also evaluated, including the evaluation of patients in Minor Response and Stable disease as well. Duration of response will be described using the stratified KM method, with strata defined by prior exposure to the different proteasome inhibitors and Immunomodulatory drugs, cytogenetic abnormalities as well as by ISS stage III versus stage I or II, including an estimate of the median, as well as the 25th and 75th percentiles, along with two-sided 95% confidence intervals.;Timepoint(s) of evaluation of this end point: 54 moths | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key secondary endpoints, including, PFS and OS will be statistically evaluated using appropriate confidence intervals. Statistical tests will be performed at the one-sided, 0.025 level. The duration of response (DOR) is defined as the duration of time measured from when response criteria were first met until the first date of recurrence or PD or death. PFS will be assessed using KM methods and OS will be assessed based on the same KM approach as used for PFS. Duration of response will be calculated, for patients achieving response (ORR), as the duration from the date when first evidence of objective disease response was achieved based on IMWG criteria, until the first date of recurrence, PD, or death. The start of DCR will be based on the date of first receipt of treatment. The duration of response for each respective type of response will be regarded as descriptive adjuncts to the analyses of response rates. Analysis of duration of each response type will be performed using stratified KM methods.;Timepoint(s) of evaluation of this end point: 54 months | — |
Countries
Spain
Contacts
Public ContactDr. Juan José Lahuerta Palacios
Fundación Pethema
Outcome results
None listed