DARATUMUMAB for Multiple myeloma

Inclusion criteria

• {"criterion_text":"- 18 to 70 years of age, inclusive.\n- Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 3 months after discontinuing study treatment (even after a successful vasectomy).\n- Male subjects of reproductive potential must not donate sperm during the study or for 3 months after the last dose of study treatment.\n- Criterion modified per Amendment 2 12.1 Signed 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. Subjects in emergency situations that do not allow for collection of informed consent are excluded.\n- Able to adhere to the prohibitions and restrictions specified in this protocol.\n- Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma and documented multiple myeloma satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria: CRAB criteria: 1. Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL) 2. Renal insufficiency: creatinine clearance <40mL/min or serum creatinine >177 μmol/L (>2 mg/dL) 3. Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL 4. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT Biomarkers of Malignancy: a. Clonal bone marrow plasma cell percentage ≥60% b. Involved: uninvolved serum FLC ratio ≥100 c. >1 focal lesion on magnetic resonance imaging (MRI) studies\n- Measurable disease as defined by any of the following: a. Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or b. Light chain multiple myeloma without measurable disease in the serum or the urine: Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda FLC ratio\n- Newly diagnosed subjects for whom high-dose therapy and autologous stem cell transplantation is part of the intended treatment plan.\n- Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 (see Attachment 1).\n- Clinical laboratory values meeting the following criteria during the Screening Phase (screening hematology and chemistry tests should be repeated if done more than 3 days before C1D1): Adequate bone marrow function: a. Hemoglobin ≥7.5 g/dL (≥4.65 mmol/L; prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is permitted however transfusions are not permitted within 7 days of randomization to achieve this minimum hemoglobin count); b. Absolute neutrophil count (ANC) ≥1.0 x 10^9/L (G-CSF use is permitted); c. Platelet count ≥50 x 10^9/L if bone marrow is >50% involved in myeloma. Otherwise ≥75 x 10^9/L Adequate liver function: a. Aspartate aminotransferase (AST) ≤2.5 x ULN; b. Alanine aminotransferase (ALT) ≤2.5 x ULN; c. Total bilirubin ≤1.5 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, direct bilirubin ≤1.5 x ULN) Adequate renal function: a. Estimated creatinine clearance ≥30 mL/min. Creatinine clearance may be calculated using Cockcroft-Gault, eGFR (Modified Diet in Renal Disease [MDRD]; Attachment 2), or CKD-epi formula b. Corrected serum calcium ≤13.5 mg/dL (≤3.4 mmol/L); or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L) (see Attachment 3) NOTE: For Criteria 7-11, contraceptive (birth control) use by men or women should be consistent with local regulations regarding the acceptable methods of contraception for those participating in clinical studies. Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for subjects in clinical studies.\n- Criterion modified per Amendment 2. 7.1 Female subjects of reproductive childbearing potential (defined as post-menarche until post-menopause unless permanently sterilized) must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the treatment period, during any dose interruptions, and for 3 months after the last dose of any component of the treatment regimen. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug and is consistent with the usual lifestyle of the subject. This birth control method must include one highly effective form of contraception (tubal ligation, intrauterine device [IUD], hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy with confirmation of procedure) 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 or bilateral oophorectomy.\n- A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing. For requirements during the Treatment Phase, refer to Section 4.3.\n- A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 3 months after receiving the last dose of any component of the treatment regimen."}

Exclusion criteria

• {"criterion_text":"- Prior or current systemic therapy or SCT for any plasma cell dyscrasia, with the exception of emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.\n- Concurrent medical or psychiatric condition or disease (such as, but not limited to, systemic amyloidosis, POEMS, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.\n- Criterion modified per Amendment 2 11.1 Any of the following: a. myocardial infarction within 6 months before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV) b. uncontrolled cardiac arrhythmia c. screening 12-lead ECG showing a baseline QT interval >470 msec (exception: subjects with pacemaker) d. screening ECHO or MUGA scan for subjects aged >65-70: left ventricular ejection fraction (LVEF) <40%\n- Received a strong CYP3A4 inducer within 5 half-lives prior to randomization (Flockhart 2016: http://medicine.iupui.edu/flockhart/)\n- Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to the Investigator's Brochure), or sensitivity to mammalian-derived products or lenalidomide or its excipients.\n- Criterion modified per Amendment 2 14.1 Not able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Subject is taking any prohibited medications as per Section 8.3. Subject is deprived of their freedom by a judicial or administrative decision, or subject is in psychiatric care. Subject is subjected to a legal protection measure or unable to provide their consent.\n- Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 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 3 months after the last dose of any component of the treatment regimen.\n- Major surgery within 2 weeks before randomization or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study. Kyphoplasty or Vertebroplasty is not considered major surgery.\n- Criterion modified per Amendment 2 17.1 Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks or 5 half-lives of the respective drug/investigational medicinal product (IMP) (whichever is longer) before randomization or is currently enrolled in an interventional investigational study.\n- Contraindications to the use of any components of the backbone treatment regimens, per local prescribing information.\n- Gastrointestinal disease that may significantly alter the absorption of oral drugs\n- 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 5.\n- Vaccination with live attenuated vaccines within 4 weeks of first study agent administration\n- Unable or unwilling to undergo antithrombotic prophylactic treatment. NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. If a subject’s clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study drug is given such that he or she no longer meets all eligibility criteria, then the subject should be excluded from participation in the study. Section 17.4, Source Documentation, describes the required documentation to support meeting the enrollment criteria.\n- Prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years of date of randomization (exceptions are adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years).\n- Criterion modified per Amendment 2 4.1 Radiation therapy for treatment of plasmacytoma within 14 days of randomization (palliative radiation for pain control secondary to lytic lesion is allowed within 14 days of randomization).\n- Plasmapheresis within 28 days of randomization.\n- Clinical signs of meningeal involvement of multiple myeloma.\n- Criterion modified per Amendment 2 7.1 Pulmonary: a. Subjects <65 years old with chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal b. Subjects ≥65 years old with a FEV1 <50% or diffusing capacity of the lungs for carbon monoxide [DLCO] <50%\n- Moderate or severe persistent asthma within the past 2 years (see Attachment 4), or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study).\n- Criterion modified per Amendment 2 9.1 Criterion modified per Amendment 4 Any of the following: a. Known to be seropositive for human immunodeficiency virus (HIV). HIV antibody testing at screening should be performed per local health guidelines. b. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [Anti-HBc] and/or antibodies to hepatitis B surface antigen [Anti-HBs]) must be screened using real-time PCR measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. c. Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy)."}

Primary endpoints

• {"endpoint_text":"- PFS is defined as the time from the date of randomization to the date of disease progression or death due to any cause, whichever occurs first.","definition_or_measurement_approach":"PFS defined as time from randomization to disease progression or death; disease progression assessed per IMWG criteria (as described in main objective)."}

Secondary endpoints

• {"endpoint_text":"- Post-consolidation MRD negativity rate, defined as the proportion of subjects who achieve MRD negativity (at or below the threshold of 10^- 5) at the end of consolidation.","definition_or_measurement_approach":"Proportion of subjects with MRD negativity ≤10^-5 at end of consolidation (as specified)."}
• {"endpoint_text":"- Overall MRD negativity rate, defined as the proportion of subjects who achieve MRD negativity (10^-5) at any time during the study.","definition_or_measurement_approach":"Proportion with MRD negativity ≤10^-5 at any time during study."}
• {"endpoint_text":"- Overall ORR, rate of VGPR or better, rate of CR or better, and rate of sCR, defined as the proportions of subjects who achieved PR or better (or VGPR or better, or CR or better, or sCR) per the IMWG criteria at post-induction, post-transplant, post-consolidation, and overall.","definition_or_measurement_approach":"Response rates (PR, VGPR, CR, sCR) assessed per IMWG criteria at specified timepoints (post-induction, post-transplant, post-consolidation, overall)."}
• {"endpoint_text":"- Progression-free survival on the next line of therapy (PFS2) is defined as the time from randomization to progression on the next line of treatment or death, whichever comes first.","definition_or_measurement_approach":"Time from randomization to progression on next line of therapy or death."}
• {"endpoint_text":"- OS, measured from the date of from randomization to the date the subject's death.","definition_or_measurement_approach":"Overall survival measured from randomization to date of death."}
• {"endpoint_text":"- Time to response (PR or better), time to CR/sCR are defined as the time from randomization to date of initial response (or initial CR/sCR,).","definition_or_measurement_approach":"Time from randomization to first documentation of PR or better (or CR/sCR)."}
• {"endpoint_text":"- Duration of response (PR or better), duration of CR, duration of sCR, and duration of MRD-negative status, are calculated from the date of the initial documentation of a response (PR or better), or CR or better, or sCR, or MRD-negative status to the date of the first documented evidence of disease progression, as defined in the IMWG criteria, or death due to PD whichever occurs first.","definition_or_measurement_approach":"Duration calculated from initial response documentation to first documented progression (IMWG criteria) or death due to PD."}
• {"endpoint_text":"- Pharmacokinetic concentrations of daratumumab (further defined in Section 9.3).","definition_or_measurement_approach":"PK sampling and concentration measurements for daratumumab as defined in protocol Section 9.3."}
• {"endpoint_text":"- Immunogenicity of daratumumab and rHuPH20","definition_or_measurement_approach":"Assessment of anti-drug antibodies to daratumumab and rHuPH20 per protocol-specified assays."}
• {"endpoint_text":"- Change in HRQoL, symptoms, and functioning using two European Organization for Research and Treatment of Cancer (EORTC) questionnaires and the EuroQol Group Five Dimensions Five Levels Questionnaires (EQ-5D-5L).","definition_or_measurement_approach":"Patient-reported outcome measures using EORTC instruments and EQ-5D-5L to assess HRQoL, symptoms and functioning."}
• {"endpoint_text":"- Stem cell yield after mobilization (further defined in Section 9.1.3.2).","definition_or_measurement_approach":"Stem cell collection yield measured per protocol definitions (see Section 9.1.3.2)."}
• {"endpoint_text":"- Time to engraftment post ASCT defined as absolute neutrophil count (ANC) ≥0.5 x 10^9/L and platelet count ≥20 x 10^9/L.","definition_or_measurement_approach":"Time to engraftment defined as date achieving ANC ≥0.5 x10^9/L and platelets ≥20 x10^9/L."}

Primary sponsor

Full Name

European Myeloma Network B.V.

Organisation Type

Patient organisation/association

Country Of Registered Address

Netherlands

Contract research organisations

Name

Parexel International (IRL) Limited

Responsibilities

Multiple sponsor duties (codes include 1,12,2,3,6,8,9) - wide CRO responsibilities including clinical operations and trial management

Name

Excelya Greece CRO Single Member S.A.

Responsibilities

Sponsor duty code:1 (clinical operations/vendor role)

Name

Perceptive Eclinical Limited

Responsibilities

eClinical services (code:3)

Name

SGS Belgium

Responsibilities

Laboratory/quality/other services (code:4)

Name

Clinigen Clinical Supplies Management

Responsibilities

Drug distribution

Third parties

• {"country":"Netherlands","full_name":"Stichting EuroQol Research Foundation","duties_or_roles":"PRO","organisation_type":"Patient organisation/association"}
• {"country":"Belgium","full_name":"SGS Belgium","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Perceptive Eclinical Limited","duties_or_roles":"code:3","organisation_type":"Pharmaceutical company"}
• {"country":"Greece","full_name":"Excelya Greece CRO Single Member S.A.","duties_or_roles":"code:1","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Adaptive Biotechnologies Corp.","duties_or_roles":"MRD assessment","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eurofins Pharma Bioanalytics Services US Inc.","duties_or_roles":"PK sample analysis at end of study","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"codes:1,12,2,3,6,8,9 (multiple sponsor duties assigned)","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services S.a.r.l.","duties_or_roles":"Lab sample handling & analysis","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"Clinigen Clinical Supplies Management","duties_or_roles":"Drug distribution","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)","duties_or_roles":"Central analysis of bone marrow samples","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"PK sample analysis at end of study","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"European Organisation For Research And Treatment Of Cancer","duties_or_roles":"PRO","organisation_type":"Patient organisation/association"}
• {"country":"United States","full_name":"EPL Pathology Archives LLC","duties_or_roles":"Long term storage facility for Janssen Biomarkers","organisation_type":"Laboratory/Research/Testing facility"}

Co-sponsors

• Emn Trial Office S.r.l. Impresa Sociale