Daratumumab As a Treatment for Adult Immune Thrombocytopenia: A Phase II Study with Safety Run-in (the DART Study)
Authors: Tsykunova Galina , Holme Pal André , Tran Hoa Thi Tuyet , Tvedt Tor Henrik Anderson , Munthe Ludvig Andre , Michel Marc , Frederiksen Henrik , Bussel James B , Kuter David J. , Ghanima Waleed 
Published: November 2021

Abstract
Background: Immune thrombocytopenia (ITP) is characterized by antibody-mediated platelet destruction and impaired platelet production. Residual long-lived autoreactive plasma cells may be a source of treatment resistance in autoimmune cytopenias. Antiplatelet-specific plasma cells have been detected in the spleen of the rituximab refractory ITP patients. These cells can also migrate and reside in bone marrow as long-lived plasma cells.
Daratumumab, an anti-CD38 antibody, targets plasma cells and is approved for the treatment of multiple myeloma. Daratumumab has been successfully used to treat refractory autoimmune cytopenias in children and a few cases of post-transplant autoimmune cytopenias and refractory SLE in adults.
We hypothesized that long-lived autoreactive plasma cells may be the source of treatment failure in some ITP patients. Based on that, we initiated a multicenter, open-label, dose-escalating phase II study with a safety run-in to evaluate the safety and efficacy of daratumumab in patients with ITP (NCT04703621). The first 3 patients were included in the safety run-in during Jan - May 2021.
Study design and methods:
Main inclusion criteria include age ≥18, primary ITP with a platelet count of ≤30X109/L, failure of corticosteroid therapy, and at least one second-line therapy including rituximab and/or TPO-RA.
Main exclusion criteria include active bleeding, secondary ITP, concomitant autoimmune hemolytic anemia.
Twenty-one patients will be included in the study. The safety run-in phase includes 3 patients who receive 4 weekly subcutaneous daratumumab injections followed by a 4-week observational period. Enrollment of the next patient in this phase occurs after the previous patient has completed treatment and an observational period. In cohort 1, 9 patients will receive 8 weekly injections. If the response rate is &lt;100% and no severe adverse events appear, the subsequent 9 patients will receive 8 weekly daratumumab injections followed by 2 injections administered every other week. Standard premedication before all daratumumab injections consists of antihistamine, corticosteroid (methylprednisolone 100 mg or equivalent before the 1 st daratumumab injection and 60 mg or equivalent before subsequent injections), and paracetamol.
Rescue ITP medications are allowed during the first 8 weeks of the study. Steroid or TPO-RA (eltrombopag or romiplostim) dosing must remain stable during the 2 weeks preceding the inclusion. Dose escalation is not allowed during the study.
The primary endpoint is a platelet count &gt;50x10 9/L in 2 measurements 12 weeks after treatment initiation for cohort 1, and 16 weeks for cohort 2, without rescue therapy after week 8. Safety will be assessed by the incidence and severity of adverse events. Secondary endpoints will include the number of weeks with platelet count &gt;50x10 9/L between the end of treatment and end of study without rescue therapy or dose increments of corticosteroids. Time to treatment failure (TTF) is defined as time to first platelet count &lt;30x10 9/L or administration of any platelet elevating therapy after achieving response.
Exploratory endpoints include: role of anti-GPIIb/IIIa and Ib antibodies; serial characterization of various subsets of immunocompetent cells in the bone marrow and blood; measurement of HRQoL and fatigue
Statistics: The primary outcome (treatment response) will be reported separately for each cohort and the entire study population, expressed by absolute numbers and rates with the corresponding 95% confidence interval. Daratumumab treatment will be considered "successful" if we observe a response rate of 30% or higher.
Current enrollment status: As of July 10, 2021, 2 sites are open. Two patients have completed the safety run-in; one is close. One/two responded to treatment at week 12. Platelet response in all 3 patients is shown in Figure 1. No serious or grade 3 adverse events were reported. Cohort 1 will start in August 2021.
Figure 1 Figure 1.

Disclosures
Tsykunova: Ablynx: Consultancy; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sobi: Consultancy; Sanofi: Consultancy. Holme: bayer, Octapharma, Pfizer: Other: support to institution, Research Funding; Bayer, Novo Nordisk, Octapharma, Pfizer, Roche, Takeda, Sobi: Consultancy, Honoraria. Tran: Astra Zeneca: Consultancy; Novartis, Janssen, Abbvie, Takeda, CSL Bering: Consultancy. Tvedt: Ablynx,Alexion, Novartis: Membership on an entity's Board of Directors or advisory committees. Michel: Amgen,Novartis,UCB,Argenx,Rigel: Honoraria. Frederiksen: Novartis: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Alexion: Research Funding; Gilead: Research Funding. Bussel: CSL: Other: DSMB; UCB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Principia/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; UptoDate: Honoraria; RallyBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova/Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Momenta/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuter: Rubius: Current equity holder in publicly-traded company; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, BioCryst, Bristol Myers Squibb (BMS), Caremark, CRICO, Daiichi Sankyo, Dova, Genzyme, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Principia, Protalex, Protalix, Rigel: Consultancy, Other: grant support and consulting fees; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Immunovant, Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ), UCB: Research Funding; Platelet Disorder Support Association: Membership on an entity's Board of Directors or advisory committees; Up-to-Date: Patents & Royalties: Up-To-Date. Ghanima: Amgen, Novartis, Pﬁzer, Bristol Myers Squibb, SOBI, Griffols, Sanoﬁ: Honoraria; Bayer, BMS/Pﬁzer: Research Funding; Amgen, Novartis, Pﬁzer, Principia Biopharma Inc- a Sanoﬁ Company, Sanoﬁ, SOBI, Griffols, UCB, Argenx: Consultancy.