Henk Lokhorst, Torben Plesner, Peter Gimsing, Hareth Nahi, Steen Lisby, Paul Richardson

Size: px

Start display at page:

Download "Henk Lokhorst, Torben Plesner, Peter Gimsing, Hareth Nahi, Steen Lisby, Paul Richardson"

Madlyn Jones
7 years ago
Views:

1 DRTUMUMB, a CD38 Monoclonal ntibody Study in dvanced Multiple Myeloma an Open-Label, Dose Escalation Followed by Open-Label Extension in a Single-rm Phase I/II Study bstract #S576 Henk Lokhorst, Torben Plesner, Peter Gimsing, Hareth Nahi, Steen Lisby, Paul Richardson University Medical Center Utrecht, Netherlands; Vejle Hospital, Denmark; Rigshospitalet, Copenhagen, Denmark; Karolinska Institutet, Stockholm, Sweden; Genmab /S, Copenhagen, Denmark; Dana-Farber Cancer Institute, Boston, M, US

Lisby, Paul Richardson University Medical Center Utrecht, Netherlands; Vejle Hospital, Denmark; Rigshospitalet, Copenhagen,

2 Disclosures Genmab: dvisory Board, research support Johnson & Johnson: dvisory Board Mundipharma: dvisory Board Celgene: Research support

3 Human CD38 mb with Broad-Spectrum Killing ctivity Human IgG1k monoclonal antibody Broad spectrum mechanisms of action including CDC, DCC, DCP, apoptosis induction and inhibition of enzymatic activity In development for multiple myeloma Here we present data from the dose-escalation (part 1) of the FIH study in patients with relapsed or relapsed and refractory multiple myeloma

$dose-escalation (part 1) of the FIH study in patients with relapsed or relapsed and refractory$

4 Objectives Primary Establishment of the safety profile of daratumumab Secondary Daratumumab: GEN501 Phase I/II Study of Monotherapy in Relapsed or Relapsed and Refractory Multiple Myeloma To establish the pharmacokinetic profile of daratumumab Evaluation of the efficacy of daratumumab according to International Myeloma Workshop Consensus Panel 1, Blood 2011;117: (IMWG) Evaluation of the immunogenicity of daratumumab

5 Main Inclusion Criteria Patients with advanced Multiple Myeloma requiring systemic therapy Patients with relapsed or relapsed and refractory disease with at least 2 prior lines of therapy and without further established treatment options Patients with ECOG performance status 0-2 Patients having a life expectancy >3 months

at least 2 prior lines of therapy and without further established treatment

6 Trial Design PRT 1 Doseescalation cohorts Open label, weekly i.v. infusion, 8 weeks Dose-escalation: 3+3 scheme mg/kg PRT 2 Expansion cohorts Ongoing Several cohorts and dose schedules are being tested - start with pre-dose at 10% of the full dose, max 10 mg - three weeks delay after first full dose - governed by independent data monitoring committee

0 mg/kg PRT 2 Expansion cohorts Ongoing Several cohorts and dose schedules are being tested - start

7 Patient Characteristics (Part 1: N=32) Cohort No. of subjects ge a No. of prior treatments Refractory to Len and Bort Len/Thal b Bort b Dex/Steroid other b Chemo b,c uto/llo b 1 mg/kg (42-76) 5 (2-8) e 88% / 71% 100% 88% / 41% 100% 65% / 12% 2 mg/kg 3 64 (60-71) 8 (6-10) e 100% / 100% 100% 100% / 100% 100% 100% / 0% 4 mg/kg 3 64 (62-66) 3 d (3-8) 67% f 100% / 33% 100% 100% / 33% 100% 67% / 33% 8 mg/kg 3 60 (56-68) 8 d (6-12) 100% f 100% / 67% 100% 100% / 67% 100% 100% / 33% 16 mg/kg 3 55 (54-59) 4 d (4-5) 67% f 100% / 67% 100% 100% / 33% 100% 100% / 67% 24 mg/kg 3 58 (50-69) 6 d (4-6) 67% f 100% / 67% 100% 100% / 33% 100% 67% / 0% PRT mg/kg (50-69) 5.5 (3-12) 75% 100% / 58% 100% 100% / 42% 100% 83% / 33% llo: allogeneic stem cell transplantation, uto: autologous stem cell transplantation, Bort: bortezomib, Chemo: chemotherapy, Len: lenalidomide, No: number, Thal: thalidomide a: median (range), b: number of patients exposed to treatment, c: vincristine, doxorubicin, cyclophosphamide, melphalan and others, d: revised after additional data collection, e: data not collected, f: data collected retrospectively

(6-10) e 100% / 100% 100% 100% / 100% 100% 100% / 0% 4 mg/kg 3 64 (62-66) 3 d (3-8) 67% f 100% / 33% 100% 100% / 33% 100% 67% / 33% 8 mg/kg 3 60 (56-68) 8 d (6-12) 100% f 100% / 67% 100% 100% / 67%

8 Infusion Related dverse Events

9 SEs ssessed Related to Daratumumab Event Bronchospasm nemia Thrombocytopenia ST > 5.2 times upper limit of normal Cytokine release syndrome PRT 1 N=32 1 patient: grade 2 (2 mg/kg) (2 days later grade 3) 1 patient: grade 2 (24 mg/kg) 1 patient: grade 3 (0.1 mg/kg) (DLT) 1 patient: grade 4 (0.1 mg/kg) 1 patient: grade 2 + grade 3 (1.0 mg/kg) (DLT) 1 patient: grade 2 (0.1 mg/kg)

mg/kg) (2 days later grade 3) 1 patient: grade 2 (24 mg/kg) 1 patient: grade 3 (0.

10 plasma conc ( g/ml) plasma conc ( g/ml) Daratumumab (Part 1) Plasma Concentration mg/kg 16 mg/kg 8 mg/kg 4 mg/kg mg/kg 1 mg/kg 0.5 mg/kg 1 LOQ time (days) time (days)

4 mg/kg 100 10 10 2 mg/kg 1 mg/kg 0.5 mg/kg 1 LOQ 0.

11 Relative change in paraprotein from baseline (%) Daratumumab Response (Part 1) Maximal Change in Paraprotein 100 < 1 mg/kg 2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg 24 mg/kg C C B C C B C B B C C Patient number : serum M-component, B: urine M-component, C: Free Light Chains (FLC)

20 0 C 19 10 12 31 16 29 8 13 C B C C B C B B C C 4 26 15 3 7 11-50 27 21 6 30 18 34 23

12 (Part 1) Response according to IMWG

13 4mg/kg (Part 1) Summary of Response Cohort (mg/kg)v N Max. reduction in M-component (%) Serum Urine Max. reduction in difference between involved and uninvolved FLC (%) Max. reduction in plasma cells in bone marrow biopsy (%) [Baseline value (%)] Response according to IMWG a [12.5] 89 [23] 97 [19] MR PR PR [14] 93 [7.5] - SD MR NE [31.5] 100 [2] PD PR SD b b [18.5] 17 [3.0] 91 [17.0] PR MR PR no measurable disease/normal at Baseline, - data not available, a Evaluation based on max. reduction in M-component or FLC, b Follow up still ongoing

reduction in plasma cells in bone marrow biopsy (%) [Baseline value (%)] Response according to IMWG a 4 3 49 100 64 87 96 80 [12.

14 Progression-Free Survival

15 Conclusion 1/2 Daratumumab has shown a favorable safety profile as monotherapy in relapsed or relapsed and refractory Multiple Myeloma patients In part 1, where 15 of 32 (47%) heavily pre-treated evaluable Multiple Myeloma patients received 8 weeks of daratumumab as monotherapy in doses up to 24 mg/kg, a reduction in paraprotein was observed In 10 of these 32 patients (31%), this reduction qualified to a clinical response: 5 patients achieving PR (15.5%) 5 patients achieving MR (15.5%) In 8 of 12 patients (67%) at doses 4 mg/kg and above achieved a clinical response: 5 patients achieving PR (42%) 3 patients achieving MR (25%)

reduction in paraprotein was observed In 10 of these 32 patients (31%), this reduction qualified to a clinical response: 5 patients achieving PR (15.

16 Conclusion 2/2 Biochemical response was accompanied by clearance of myeloma cells from the bone marrow t higher dose levels, observed plasma concentrations are close to those predicted Overall increased daratumumab exposure correlated with longer progression free survival Further studies: We are currently exploring an 8 mg/kg weekly schedule but will also explore other doses and different schedules

increased daratumumab exposure correlated with longer progression free survival Further studies: We

17 cknowledgments Special thanks to investigators, sub-investigators, research staff and patients and their families at the collaborating centers: Karolinska Institutet, Stockholm, Sweden Rigshospitalet, Copenhagen, Denmark University Medical Center Utrecht, Netherlands Vejle Hospital, Denmark Dana-Farber Cancer Institute, Boston M, US

Institutet, Stockholm, Sweden Rigshospitalet, Copenhagen, Denmark University

DARATUMUMAB, A CD38 MONOCLONAL ANTIBODY IN PATIENTS WITH MULTIPLE MYELOMA - DATA FROM A DOSE- ESCALATION PHASE I/II STUDY

DARATUMUMAB, A CD38 MONOCLONAL ANTIBODY IN PATIENTS WITH MULTIPLE MYELOMA - DATA FROM A DOSE- ESCALATION PHASE I/II STUDY Torben Plesner, Henk Lokhorst, Peter Gimsing, Hareth Nahi, Steen Lisby, Paul Richardson