Ensayos clínicos

Inclusion Criteria:

Signed Written Informed Consent

• Voluntary signed and dated IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not a part of standard of care.

Target Population

• ECOG Performance of 0 or 1.
• Subjects must meet the following:
  • Must have measurable disease as measured by presence of monoclonal immunoglobulin protein in a serum electrophoresis: IgG, IgA, IgM, (M-protein ≥ 0.5 g/dl), OR urine M-protein ≥ 200 mg/24-hour collection sample, OR involved serum free-light chain (sFLC) ≥ 100 mg/L provided FLC ratio is abnormal ii) Must have corrected serum calcium < 11.5 mg/dL within 2 weeks of randomization;
  • Must consent to bone marrow aspirate or biopsy;
  • Must be at least 14 days from use of prior anti-myeloma therapy (approved therapies), and at least 28 days or 5 half-lives, whichever is longer, from use of any experimental drug therapy or plasmapheresis. Bisphosphonates use is permitted if initiated prior to the first dose of study medication.
  • Must be more than 12 weeks post autologous transplant.
• Must meet one of the criteria below:
  • Subject has received at least 3 prior lines of therapy including a proteasome inhibitor [PI] and an immunomodulatory agent [IMiD]; OR
  • Subject has disease that is double refractory to a PI and an IMiD*.
  • * NOTE: Refractory is defined as disease progression on or within 60 days of treatment with a PI and an IMiD, given in the same or different lines of therapy.
• Prior palliative radiation must have been completed at least 2 weeks prior to study Day 1.
• Toxicities related to prior therapy must have returned to Grade 1 or less, except for alopecia. Peripheral neuropathy must be Grade 1 or less.
• Adequate bone marrow function defined as:
  • Absolute neutrophil count ≥ 1000/µl (no growth factor within 1 week of study drug administration; no pegylated growth factors within 3 weeks of first drug administration);
  • Hemoglobin ≥ 8 g/dL. No transfusions are allowed within 72 hours prior to qualifying  laboratory value. Recombinant human erythropoietin not permitted within 3 weeks of study drug administration.
  • Platelet count ≥ 75 X 103/µl or > 30 x 103/µL if  ≥ 50% of bone marrow nucleated cells were plasma cells. Qualifying laboratory value must occur at the most recent measurement prior to study entry. No transfusion to achieve this level is permitted within 72 hours prior to qualifying laboratory value.
• Adequate renal parameters defined as:
  • Creatinine clearance (CrCl) ≥ 30 ml/min measured by 24-hour urine collection or estimated by the Cockcroft-Gault formula.
• Adequate hepatic parameters defined as:
  • AST < 3 x ULN;
  • ALT < 3 x ULN;
  • Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert’s Syndrome, who must have a total bilirubin < 3.0 mg/dL and direct bilirubin < 0.5 mg/dL.
• Ability to comply with treatment, PK, and immune-monitoring sample collection (when indicated) and required study follow up.

Age and Reproductive Status

• Men and women ≥ 18 years of age.
• Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception from the time of enrollment through the duration of treatment with study drug plus 5 months after the last dose of investigational product. 
• Women of childbearing potential (WOCBP) must have 2 negative serum or urine pregnancy tests (minimum sensitivity 25 IU/L or equivalent units of HCG): one 10-14 days prior to start of the study drug, and another within 24 hours prior to the start of study drug.
• Women must not be breastfeeding.
• Sexually active fertile men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 7 months after the last dose of investigational product.
• Azoospermic males and WOCBP who are not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section.
• Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
• Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as listed in the informed consent document.

Exclusion Criteria:

Target Disease Exceptions

• Subjects with a history of central nervous system involvement by hematologic malignancy or symptoms suggestive of central nervous system involvement.
• Subjects are excluded if they have:
  • Solitary bone or extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia;
  • Monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), primary amyloidosis, Waldenstrom’s macroglobulinemia, or POEMS syndrome (plasma cell dyscrasia with poly neuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes);
  • Active plasma cell leukemia (defined as either 20% of peripheral blood white blood cell count comprised of plasma/CD138+ cells or an absolute plasma cell count of 2 x 109/L).

Medical History and Concurrent Diseases

• Subjects with concomitant second malignancies (except adequately treated non-melanomatous skin cancers, melanoma in situ surgically resected, carcinoma in situ of the breast, superficial bladder cancer, prostate cancer or in situ cervical cancers) are excluded unless a complete remission was achieved as it is empirically determined based on the malignancy and treatment provided prior to study entry and no additional therapy is required or anticipated to be required during the study period.
• Subjects with an active, known, or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• A serious uncontrolled medical disorder or active infection which would impair the ability of the subject to receive protocol therapy or whose control may be jeopardized by the complications of this therapy.
• Deep vein thrombosis not adequately controlled.
• Uncontrolled or significant cardiovascular disease including, but not limited to any of the following:
  • Myocardial infarction or stroke/TIA within the past 12 months;
  • Unstable or poorly controlled angina within the past 3 months;
  • Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation or torsades de pointes);
  • QTc prolongation > 480 msec;
  • History of other clinically significant heart disease (i.e., cardiomyopathy, congestive heart failure with NYHA functional classification III-IV, pericarditis, significant pericardial effusion);
  • Requirement for daily supplemental oxygen therapy.
• Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti CTLA-4 antibody (or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways).
• Prior organ allograft or allogeneic bone marrow transplantation.
• Any of the following:
  • Prior treatment with anti CD38 monoclonal antibodies.
• Treatment with corticosteroids within 2 weeks of the first dose of study drug, except for the equivalent of ≤ 10 mg prednisone per day or corticosteroids with minimal to no systemic absorption (i.e., topical or inhaled steroids) or for short course (≤ 4 days) of 40 mg dexamethasone or equivalent for emergency use (baseline M proteins must be drawn after this short course and prior to randomization). Adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Major cardiac surgery within 8 weeks prior to the first dose of study drug; all other major surgery within 4 weeks prior to the first study drug dose. Kyphoplasty is not considered major surgery; subjects should have been fully recovered from any surgical related toxicities.
• Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal.
• Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
• Vaccination with live attenuated vaccines within 4 weeks of first study agent administration.

Physical and Laboratory Test Findings

• Positive for human immunodeficiency virus (HIV 1/2) antibody (may obtain additional testing or substitute testing per institutional guidelines to rule out infection), or known acquired immunodeficiency syndrome (AIDS).
• Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [antiHBc] and/or antibodies to hepatitis B surface antigen [antiHBs]) must be screened using real-time polymerase chain reaction (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 (antiHBs 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.
• 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).

Allergies and Adverse Drug Reaction

• History of Grade 4 anaphylactic reaction to monoclonal antibody therapy.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the daratumumab formulation.

Other Exclusion Criteria

• Prisoners or subjects who are involuntarily incarcerated.
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
• Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria. No exception to the entry criteria is permitted.