The DART Study- Daratumumab Treatment in ITP
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Intervention ( safety run-in, cohort 1, cohort 2) 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
subcutaneious daratumumab administration
Other Names:
|
Outcome Measures
Primary Outcome Measures
- to evaluate of response after daratumumab treatment [12-16 weeks]
Response defined as platelet count ≥50 x109/L in 2 measurements (taken at least 24 hours apart) during week 12 for 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.
- safety of daratumumab [24 weeks]
incidence, severity and relationship of treatment emergent adverse events
Secondary Outcome Measures
- time to response [12-16 weeks]
Time to response defined as time from first daratumumab injection to first platelet count >50 X 109/L
- duration of response [minimum 24 weeks]
defines as median number of weeks with platelet count ≥50 x109/Lbetween end of treatment and end of study/ week 24 without having received rescue therapy or having had dose increment of corticosteroids in the 4 weeks prior to the first platelet count >50x109/L
- time to treatment failure [24 weeks]
defines as first platelet count <30x109/L or administration of any platelet elevating therapy after achieving response
- measurement of HRQoL and fatigue [24 weeks]
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
- measurements of antibodies [24 weeks]
level of anti-GPIIb/IIIa and Ib antibodiesbefore daratumumab therapy and at study week 24
- analysis of platelet bound antibodies and functional testing of immunocompetent cells [24 weeks]
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
- measurements of various subsets of immunocompetent cells [24 weeks]
characterization of various subsets of immunocompetent cells in the bone marrow and blood before daratumumab therapy and at study week 24
- correlation between response and changes in antibody levels or of immunocompetent cells. [24 weeks]
identify whether or not changes to antibody levels or of immunocompetent cells correlate with clinical response
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male or female aged ≥18 years.
-
Primary ITP with a platelet count of ≤30 X 109/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 >12 weeks ago and/or TPO-RA. For the safety run-in phase, a platelet count of 15-30 X 109/L will be required
-
Signed and dated written informed consent.
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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. condom with spermicidal foam/film/gel/cream/ suppository, and all men must also not donate sperm during the study and for 3 month following discontinuation of Daratumumab (for details see appendix VII)
Exclusion Criteria:
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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
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Pregnancy or lactation
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Surgery planned within the 3 next months
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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
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Concomitant autoimmune hemolytic anemia
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Known allergy and/or sensitivity or contraindication to daratumumab
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Active malignancy with the exception of basal and squamous carcinoma of the skin, in situ cervical cancer. Low grade (Gleason 3+3 or less) prostate cancer or in situ breast carcinoma if surgically treated.
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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.
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Patient unable to attend all the visits planned for the trial
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Known previous infection or seropositivity for Hepatitis B
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Odense University Hospital | Odense | Denmark | 5000 | |
| 2 | Henri Mondor University Hospital | Créteil | France | ||
| 3 | Haukeland University Hospital | Bergen | Norway | ||
| 4 | Ostfold Hospital Trust | Grålum | Norway | 1714 | |
| 5 | Akershus University Hospital | Oslo | Norway | ||
| 6 | Oslo University Hospital | Oslo | Norway |
Sponsors and Collaborators
- Ostfold Hospital Trust
- Haukeland University Hospital
- Oslo University Hospital
- University Hospital, Akershus
- Henri Mondor University Hospital
- Odense University Hospital
Investigators
- Principal Investigator: Waleed Ghanima, PhD, Ostfold Hospital Trust
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- RGCH005