The DART Study- Daratumumab Treatment in ITP

Study Overview
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Brief Summary
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A multicenter clinical, open-label total dose-escalating phase II study with safety run-in to explore the clinical activity, total dosage, and safety of daratumumab in adult ITP patients who have not responded adequately or relapsed after corticosteroids and at least one second-line therapy including rituximab and/or TPO-RA.

Detailed Description
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Many patients with chronic ITP require repeated or continuous medications to maintain a safe platelet count. B-cell depletion with rituximab in ITP induces the differentiation of short-lived auto-immune plasma cells into pathogenic long-lived plasma cells in the spleen that was not present before treatment. It has been reported that refractory ITP is related to the presence of long-lived plasma cells, which are resistant to steroids and immunosuppressants, including rituximab. These findings lead to the hypothesis that therapy directed against plasma cells may help overcome treatment resistance. At least in a proportion of patients, treatment resistance is caused by CD20 negative long-lived plasma cells. This study aims to investigate the efficacy, the optimal number of treatments, and safety of anti-CD38 antibody daratumumab steroid-refractory or steroid-dependent in ITP patients who fail to respond to at least one previous second-line therapy, including rituximab and/ or TPO agonist.

Official Title
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Daratumumab as a Treatment for Adult Immune Thrombocytopenia (The DART Study)

Conditions
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ITP

Intervention / Treatment
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* Drug: Daratumumab Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged ≥18 years. Primary ITP with a platelet count of ≤30x109/L measured within 2 weeks prior to inclusion with failure to achieve response or relapse after corticosteroid therapy, and at least one second-line therapy including rituximab (last infusion ≥ 24 weeks before study inclusion) and/or TPO-RA. The dose of steroids or/and TPO-RAs (romiplostim, eltrombopag and avatrombopag) has not been changed during the last 2 weeks preceding the inclusion. For the safety run-in phase, a platelet count of 15-30x 109/L will be required. Signed and dated written informed consent. Females of child-bearing potential accepting to follow effective contraceptive methods for at least 24 weeks following the administration of first daratumumab injection. A man who has not had a vasectomy and who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control e.g., a condom with spermicidal foam/film/gel/cream/suppository, and all men must also not donate sperm during the study and for 3 months following discontinuation of Daratumumab Exclusion Criteria: Patients with active bleeding during the last 7 days prior to inclusion. Active bleeding is defined as any clinically overt hemorrhage (including radiologically diagnosed bleeding) with ongoing hemoglobin fall or bleeding requiring immediate intervention. Pregnancy or lactation. Surgery planned within the 3 next months. Secondary ITP: ITP associated with lymphoma, chronic lymphocytic leukemia, drug induced or ITP secondary to autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome, common variable immune deficiency, human immunodeficiency virus, or hepatitis C. Concomitant autoimmune hemolytic anemia. Known allergy and/or sensitivity or contraindication to daratumumab. Current active malignancy likely to require chemotherapy or surgical treatment during the study period or within one year after the start of the study treatment. Patients with history of poor compliance or history of alcohol/drug abuse or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent. Patient unable to attend all the visits planned for the trial. Positive at screening for hepatitis B virus (HBV) surface and core antibodies unrelated to vaccination: patients with positive HBV surface antigen (HbsAg) are not eligible patients who are HbsAg negative and HBV core antigen antibody positive (HBcAb) will be tested for HBV surface antibody (HBsAb) and HBV DNA. If HBsAb titer is >1000 IU/ml, patients may be enrolled. Monthly HBV DNA monitoring will be required while on treatment and for the 6 months after the last dose of the study drug. patients who are HBcAb positive, HBsAg negative with HBsAb titer <100 IU/ml or negative, are not eligible. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD. Known moderate or severe persistent astma within the past 2 years, uncontrolled asthma of any classification. Patient participating in another clinical trial with an investigational drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: The first 3 patients will be included in the safety run-in phase. The next 9 patients will be included in cohort 1 to receive 8 weekly injections. If the response rate is less than 100%, the next 9 patients will be included in cohort 2 to receive 8 weekly injections followed by 2 bi-weekly injections.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention ( safety run-in, cohort 1, cohort 2)<br>Safety run-in( 3 patients): daratumumab once a week x 4 doses. If no worsening of thrombocytopenia can be attributed to study treatment or any other life-threatening events, the study will proceed to the main part. Cohort 1 ( 9 patients): daratumumab once a week x 8 doses If response is <100%: Cohort 2 ( 9 patients): daratumumab once a week x 8 doses followed by daratumumab every 2 weeks x 2 doses | Drug: Daratumumab Injection<br>* subcutaneious daratumumab administration<br>* Other names: Darzalex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| to evaluate of response after daratumumab treatment | Response defined as platelet count ≥50 x109/L in 2 measurements (taken at least 24 hours apart) during week 12 for safety run-in cohort 1 and during week 16 for cohort 2 (after first study drug injection) without having received rescue therapy, having had dose increment of TPO-RA or corticosteroids during the study period. | 12-16 weeks | 
| safety of daratumumab | incidence, severity and relationship of treatment emergent adverse events | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| duration of respons (DOR) | duration of sustained platelet count ≥50x109/L without having received any platelet elevating therapy or having had dose increment of TPO-RA and/or corticosteroids | 12-16 weeks | 
| time to treatment failure (TTF) | time with platelet count≥ 50x109/L from 4 weeks after the last daratumumab injection to the first platelet count <30x109/L of two counts taken in two consecutive measurements at least 24 hours apart, or administration of any platelet elevating therapy after achieving response | minimum 24 weeks | 
| measurement of HRQoL and fatigue | measurement of HRQoL and fatigue using SF36 and MFI-20 questionnaire before daratumumab therapy, at week 8 for safety run-in, at week 12 for cohort 1, at week 16 for cohort 2 and at study week 24 for all patients in the study. Assess of difference in HRQoL and fatigue between non-responders and responders prior to and after daratumumab treatment | 24 weeks | 
| measurements of antibodies | level of anti-GPIIb/IIIa and Ib antibodiesbefore daratumumab therapy and at study week 24 ( only Norwegian centers) | 24 weeks | 
| analysis of platelet bound antibodies and functional testing of immunocompetent cells | analysis of platelet bound antibodies and functional testing of immunocompetent cells in peripheral blood and bone marrow before daratumumab therapy and at study week 24 ( only Norwegian centers) | 24 weeks | 
| measurements of various subsets of immunocompetent cells | characterization of various subsets of immunocompetent cells in the bone marrow and blood before daratumumab therapy and at study week 24(only Norwegian centers) | 24 weeks | 
| correlation between response and changes in antibody levels or of immunocompetent cells. | identify whether or not changes to antibody levels or of immunocompetent cells correlate with clinical response ( only Norwegian centers) | 24 weeks |