Daratumumab for Treatment of Proliferative Glomerulonephritis With Monoclonal Immune Deposits

Inclusion Criteria:

• Renal biopsy read at Mayo Clinic confirming the diagnosis of PGNMID

• Proteinuria ≥ 1000 mg over 24 hours

• Creatinine clearance ≥ 20 mL/min/SA

• Subjects able and willing to give informed consent

• For female subjects of reproductive childbearing potential must commit to eitherabstain continuously from heterosexual sexual intercourse or to use 2 methods ofreliable birth control simultaneously during the Treatment Period, during any doseinterruptions, and for 3 months after the last dose of any component of thetreatment regimen. Sexual abstinence is considered a highly effective method only ifdefined as refraining from heterosexual intercourse during the entire period of riskassociated with the study drug. This birth control method must include one highlyeffective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings, or implants] orpartner's vasectomy) and one additional effective contraceptive method (male latexor synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeksprior to dosing. Reliable contraception is indicated even where there has been ahistory of infertility, unless due to hysterectomy or bilateral oophorectomy

• A woman of childbearing potential must have 2 negative serum or urine pregnancytests at Screening, first within 10 to 14 days prior to dosing and the secondwithin 24 hours prior to dosing.

• A woman must agree not to donate eggs (ova, oocytes) for the purposes ofassisted reproduction during the study and for a period of 3 months afterreceiving the last dose of any component of the treatment regimen.

• For male subjects of reproductive potential who are sexually active with females of

• reproductive potential must always use a latex or synthetic condom during thestudy and for 3 months after discontinuing study treatment (even after asuccessful vasectomy).

• Male subjects of reproductive potential must not donate sperm during the studyor for 3 months after the last dose of study treatment.

• Must sign an informed consent form (ICF) or their legally acceptablerepresentative must sign indicating that he or she understands the purpose of,and procedures required for, the study and is willing to participate in thestudy.

Exclusion Criteria:

• Pregnant or planning to become pregnant

• Seropositive for human immunodeficiency virus (HIV)

• Seropositive for hepatitis C (except in the setting of a sustained virologicresponse [SVR], defined as aviremia at least 12 weeks after completion of antiviraltherapy).

• Seropositive for hepatitis B (defined by a positive test for hepatitis B surfaceantigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAgnegative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/orantibodies to hepatitis B surface antigen [anti-HBs]) will also be excluded.Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivityas the only serologic marker) AND a known history of prior HBV vaccination, do notneed to be tested for HBV DNA by PCR and can be included.

• Multiple myeloma defined as >10% plasma cells on bone marrow biopsy and M-spike > 3g/dL and presence of myeloma defining event (hypercalcemia, cast nephropathy, bonedisease, or anemia), or plasma cells >60% or FLC ratio of involved to uninvolved > 100

• Abnormal clinical labs defined as: anemia with Hgb < 8.0 g/dL, thrombocytopenia withplatelet count < 75,000, leukopenia with WBC < 3.5, or neutropenia with ANC < 1000,AST/ALT > 2.5 X ULN, bilirubin > 2 X ULN

• Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required forparticipants suspected of having COPD and participants must be excluded if FEV1 is < 50% of predicted normal.

• Moderate or severe persistent asthma withing the past 2 years or uncontrolled asthmaof any classification. Note the participants who currently have controlledintermittent asthma or controlled mild persistent asthma are allowed to participate.

• Clinically significant cardiac disease including:

• Myocardial infarction within 6 months before randomization, or unstable oruncontrolled disease/condition related to cardiac dysfunction (e.g., unstableangina, congestive heart failure, New York Heart Association Class III-IV)

• Uncontrolled arrythmia

• Prior or current exposure to any of the following:

• To daratumumab or other anti-CD-38 therapies (unless a re-treatment study)

• Exposure to an investigational drug (including investigational vaccine) orinvasive investigational medical device for any indication within 4 weeks or 5pharmacokinetic half-lives, whichever is longer.

• Focal radiation therapy within 14 days prior to randomization with theexception of palliative radiotherapy for symptomatic management but not onmeasurable extramedullary plasmacytoma.

• Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding giving reasonable suspicion of a disease or condition thatcontraindicates the use of an investigational drug or that may affect theinterpretation of the results or render the patient at high risk from treatmentcomplication

• Unable to provide consent

• Patients receiving therapy with oral prednisone or glucocorticoid equivalent in thelast 4 weeks. Patients treated with low dose oral prednisone or glucocorticoid areallowed to be included if they are taking the medication for conditions unrelated toPGNMID (e.g., asthma, gout) at a daily dose of 10mg or less.

• Patients who had received immunosuppressive therapy with MMF, cyclosporine,tacrolimus, or azathioprine in the last 3 months. For patients who have shown noreduction in proteinuria despite ≥ 3 months of MMF, AZA, cyclosporine, tacrolimus,etc, are allowed to enter the study after discontinuing these meds for 7 or moredays.

• Patients who have received cyclophosphamide or bortezomib will be allowed toparticipate as long as there is clear evidence of lack of response tocyclophosphamide or bortezomib defined as lack of achieving complete or partialremission.

• Patients who received rituximab previously with CD20 count of < 20 cells/microliterat the time of enrollment

• Have received vaccination with live attenuated vaccines within 4 weeks of firststudy agent administration

• A history of malignancy (other than multiple myeloma) unless all treatment of thatmalignancy was completed at least 2 years before consent and the patient has noevidence of disease before the date of randomization. Exceptions are squamous andbasal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, orother non-invasive lesion that in the opinion of the investigator, with concurrencewith the sponsor's medical monitor, is considered cured with minimal risk ofrecurrence within 3 years.