Ensayos clínicos

Inclusion Criteria:

• Subject must be at least 18 years of age.
• Subject must have had documented multiple myeloma as defined by the criteria below:
  • Monoclonal plasma cells in the bone marrow ≥ 10% at some point in their disease history, or presence of a biopsy-proven plasmacytoma.
• Measurable disease at Screening as defined by any of the following:
  • IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL or urine M-protein level ≥ 200 mg/24 hours; or IgA, IgD, IgE, IgM multiple myeloma: serum M-protein level ≥ 0.5 g/dL 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 ≥ 10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
• Subject must have received at least 1 prior line of therapy for multiple myeloma.
  • NOTE: A "line of therapy" is defined as 1 or more cycles of a planned treatment program.
• Subject must have documented evidence of progressive disease (PD) based on investigator’s determination of response by the IMWG criteria on or after their last regimen.
• Subject must have achieved a response (partial response [PR] or better based on investigator’s determination of response by the IMWG criteria) to at least 1 prior regimen in the past.
• Subject must have an ECOG Performance Status score of 0, 1, or 2.
• For subjects experiencing toxicities resulting from previous therapy (including peripheral neuropathy), the toxicities must be resolved or stabilized to ≤ Grade 1.
• 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 [IUD], 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.
• A woman of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to randomization.
• Each subject (or their legally acceptable representative) must sign an Informed Consent Form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.

Exclusion Criteria:

• Subject has received daratumumab or other anti-CD38 therapies previously.
• Subject is refractory to VELCADE, or another PI, like ixazomib and carfilzomib (i.e., subject had progression of disease while receiving VELCADE therapy or within 60 days of ending VELCADE therapy, or another PI therapy, like ixazomib and carfilzomib).
• Subject is intolerant to VELCADE (i.e., discontinued due to any adverse event while on VELCADE treatment.
• Subject has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic halflives of the treatment, 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) before treatment. A list of anti-myeloma treatments with the corresponding pharmacokinetic half-lives is provided in the Site Investigational Product Procedures Manual (IPPM).
• Subject has received ASCT within 12 weeks before the date of randomization, or the subject has previously received an allogenic stem cell transplant (regardless of timing).
• Subjects planning to undergo a stem cell transplant prior to progression of disease on this study, ie, these subjects should not be enrolled in order to reduce disease burden prior to transplant.
• Subject has a history of malignancy (other than multiple myeloma) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin and 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).
• Subject has known meningeal involvement of multiple myeloma.
• Criterion modified per amendment INT-1.
• Subject has peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) most recent version.
• Subject has either of the following:
  • Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal;
  • Known moderate or severe persistent asthma, or a history of asthma within the last 2 years (see Attachment 8), or currently has uncontrolled asthma of any classification.
    • (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study).
• Subject is known to be seropositive for human immunodeficiency virus (HIV) or known to have hepatitis B surface antigen positivity, or known to have a history of hepatitis C.
• Subject has any concurrent medical condition or disease (e.g., active systemic infection) 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.
• Subject has clinically significant cardiac disease, including: 
  • Myocardial infarction within 6 months before date of randomization, or unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV).
  • Uncontrolled cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] [most recent version] Grade 2 or higher) or clinically significant ECG abnormalities.
  • Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msec.
• Subject has any of the following laboratory test results during the Screening Phase:
  • Absolute neutrophil count ≤ 1.0 × 109/L;
  • Hemoglobin level ≤ 7.5 g/dL (≤5 mmol/L) (it is not permissible to transfuse a subject to reach this level);
  • Platelet count < 75 × 109/L for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count <50 × 109/L (it is not permissible to transfuse a subject to reach this level);
  • Alanine aminotransferase level ≥ 2.5 times the upper limit of normal (ULN);
  • Aspartate aminotransferase ≥ 2.5 x ULN;
  • Total bilirubin level ≥ 1.5 × ULN, (except for Gilbert Syndrome: direct bilirubin 1.5 × ULN);
  • Creatinine clearance ≤ 20 mL/min/1.73 m2 (may be calculated using the Cockcroft-Gault formula, Modification of Diet in Renal Disease [MDRD] formula or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula, provided in Attachment 3), or measured);
  • Serum calcium corrected for albumin >14.0 mg/dL (> 3.5 mmol/L), or free ionized calcium 6.5 mg/dL (> 1.6 mmol/L).
• Subject has known allergies, hypersensitivity, or intolerance to VELCADE, monoclonal antibodies or human proteins, or their excipients (refer to most recent Package Insert for VELCADE and/or Investigator’s Brochure Daratumumab,18 or known sensitivity to mammalian-derived products.
• Subject has plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential) or Waldenström’s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis.
• Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.
• Subject is a woman who is pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug.
• Subject has received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before randomization (except for investigational anti-myeloma agents, which cannot be taken within 2 weeks prior to randomization).
• Subject has had major surgery within 2 weeks before randomization, or has not fully recovered from an earlier surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration. Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery.
  • NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. If a subject's status changes (including laboratory results or receipt of additional medical records) after screening but before the first dose of study treatment is given such that he or she no longer meets all eligibility criteria, then the subject should be excluded from participation in the study.
• Source Documentation, describes the required documentation to support meeting the enrollment criteria. Subjects who fail to meet the inclusion and exclusion criteria (i.e., screen failures) may be rescreened if their condition changes. Rescreening must be discussed with and approved by the sponsor on a case-by-case basis. Subjects who are determined to be eligible for rescreening must sign a new ICF and will then be assigned a new Screening number.