DAratumumab iN combination with BorTEzomib and Dexamethasone in subjects with relapsed or relapsed and refractory Multiple Myeloma and severe renal impairment including subjects undergoing hemodialysis. A phase 2, open-label, multicenter trial

Phase 1

Conditions: Multiple Myeloma
MedDRA version: 20.0Level: PTClassification code 10035226Term: Plasma cell myelomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2016-000433-51-DE

Lead Sponsor: niversity Medical Center Hamburg-Eppendorf

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 36

Inclusion Criteria

1.Subjects must be at least 18 years of age
2.Written informed consent
3.Subjects must have had documented multiple myeloma requiring treatment as defined by the criteria below:
Monoclonal plasma cells in the bone marrow > 10% and/or presence of a biopsy-proven plasmacytoma at some point in their disease history requiring treatment according diagnostic criteria (IMWG updated criteria 2014, Rajkumar et al. 2014) see appendix I
With measurable disease at screening (serum M-protein > 500 mg/dl or urine M-protein > 200 mg/24h, in case of oligosecretory MM serum free light chain > 10 mg/dl and abnormal kappa/lambda free light chain ratio)
4.GFR < 30 ml/min and /or subjects undergoing hemodialysis
5.Subject must have received at least 1 prior treatment line
6.Subjects must have documented evidence of progressive disease after the last treatment line
7.ECOG performance status 0-3 (ECOG 3 is only allowed if due to myeloma disease)
8.Subjects must have certain pretreatment laboratory values meeting the following criteria during the Screening Phase:
a)Hemoglobin =7.5 g/dl (4,66 mmol/L; prior red blood cells (RBC) transfusion or recombinant human erythropoietin use is permitted).
b)Absolute neutrophil count = 1.0 x109/L (granulocyte colony stimulating factor (GCSF) use is permitted);
c)Platelet count more or equal 70 x109/L for subjects in whom ? 50% of bone marrow nucleated cells are plasma cells; otherwise platelet count ? 50 x 109/L (transfusions are not permitted to achieve this minimum platelet count ),
d)Aspartate aminotransferase (AST) = 2,5 x upper limit of normal (ULN);
e)Alanine aminotransferase (ALT) = 2,5 x ULN
f)Total bilirubin = 2.0 x ULN ,except in subjects with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin = 2.0 x ULN
g)Corrected serum calcium = 14 mg/dl (=3,5mmol/L); or free ionized calcium ? 6,5 mg/dL(?1,6 mmol/L)
9.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.
10.A woman of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to treatment start.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 20
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 16

Exclusion Criteria

1.Subject has received prior Daratumumab or other Anti-CD38 antibodies (previous treatment with Elotuzumab is allowed)
2.Evidence of intolerance to bortezomib or known allergies, hypersensitivity or intolerance to monoclonal antibodies
3.Subject has received anti-myeloma treatment within 2 weeks of Cycle 1, day 1. 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.
4.Active graft-versus host disease under immunosuppressive treatment
5.Subject is a woman who is pregnant or breastfeeding
6.Prior invasive malignancy within 5 years before trial inclusion
7.Active, uncontrolled infection.
8.Subject has peripheral neuropathy = 3 or neuropathic pain Grade 2 or higher
9.Subject has either of the following:
a. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is only required for subjects suspected of having COPD
b. Known moderate or severe persistent asthma, 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).
10.Subject has clinically significant cardiac disease, including myocardial infarction within 6 months before date of study entry, unstable angina, cardiac insufficiency New York Heart Association (NYHA) Class III-IV or uncontrolled arrhythmia
11.Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined significant is defined by presence of serum M-protein ? 3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia and renal insufficiency related to M-protein; and (if determined) proportion of plasma cells in the bone marrow of 10% or less (Kyle et al. 2003). Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with absence of related organ or tissue impairment and organ damage (Kyle et al., 2003, 2007).
12.Subject has a diagnosis of Waldenström’s disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
13.Subject has had radiation therapy within 14 days of treatment
14.Subject has had plasmapheresis within 14 days of treatment. Screening laboratory values have to be performed after end of plasmapheresis.
15.Subject is known to be seropositive for 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 antigen (anti HBs and anti HBc respectively), or hepatitis C (anti-HCV antibody positive or HCV RNA quantitation positive).
16.Subject has had major surgery within 2 weeks before treatment und has not fully recovered from surgery, or has surgery panned during the time the subject is expected to participate in the study.
17.Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs
18.Subject has any concurrent medical or psychiatric condition or disease (eg. 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 the participating in

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Evaluate the efficacy (overall response rate, ORR according to IMWG recommendations) of the combination of Daratumumab, Bortezomib and Dexamethasone in subjects with relapsed and refractory MM and impaired renal function;Secondary Objective: Evaluate progression-free survival (PFS)<br>Evaluate overall survival (OS)<br>Evaluate renal efficacy according to IMWG (Dimopoulos et al., 2010) history of renal impairment will be documented in the eCRF<br>Evaluate safety and tolerability of DVd as assessed by the incidence of clinical and laboratory toxicities<br>Evaluate pharmacokinetics (Serum concentration of Daratumumab)<br>;Primary end point(s): overall response rate;Timepoint(s) of evaluation of this end point: evaluation of response at each cycle

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Evaluate safety and tolerability as assessed by the incidence of clinical and laboratory toxicities<br>Evaluate progression-free survival (PFS)<br>Evaluate overall survival (OS)<br>Evaluate renal efficacy according to IMWG (Dimopoulos, MA et al. 2010) Evaluate pharmacokinetics (Serum concentration of Daratumumab)<br>;Timepoint(s) of evaluation of this end point: Evaluate safety and tolerability as assessed by the incidence of clinical and laboratory toxicities<br>Evaluate progression-free survival (PFS)<br>Evaluate overall survival (OS)<br>Evaluate renal efficacy according to IMWG (Dimopoulos, MA et al. 2010) Evaluate pharmacokinetics (Serum concentration of Daratumumab)<br>

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