Clinical trial NCT04703621: The DART Study- Daratumumab Treatment in ITP
Official title: Daratumumab as a Treatment for Adult Immune Thrombocytopenia (The DART Study)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: ITP
Lead sponsor: Ostfold Hospital Trust
Sponsor class: OTHER
Collaborators: name: Haukeland University Hospital
name: Oslo University Hospital
name: University Hospital, Akershus
name: Henri Mondor University Hospital
name: Odense University Hospital
First posted: 2021-01-11
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

1. Male or female aged ≥18 years.
2. 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.
3. Signed and dated written informed consent.
4. 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:

1. 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.
2. Pregnancy or lactation.
3. Surgery planned within the 3 next months.
4. 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.
5. Concomitant autoimmune hemolytic anemia.
6. Known allergy and/or sensitivity or contraindication to daratumumab.
7. 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.
8. 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.
9. Patient unable to attend all the visits planned for the trial.
10. 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.
11. 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.
12. Known moderate or severe persistent astma within the past 2 years, uncontrolled asthma of any classification.
13. Patient participating in another clinical trial with an investigational drug.

Primary outcomes:
measure: to evaluate of response after daratumumab treatment
timeFrame: 12-16 weeks
measure: safety of daratumumab
timeFrame: 24 weeks
Secondary outcomes:
measure: duration of respons (DOR)
timeFrame: 12-16 weeks
measure: time to treatment failure (TTF)
timeFrame: minimum 24 weeks
measure: measurement of HRQoL and fatigue
timeFrame: 24 weeks
measure: measurements of antibodies
timeFrame: 24 weeks
measure: analysis of platelet bound antibodies and functional testing of immunocompetent cells
timeFrame: 24 weeks
measure: measurements of various subsets of immunocompetent cells
timeFrame: 24 weeks
measure: correlation between response and changes in antibody levels or of immunocompetent cells.
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Odense
country: Denmark
facility: Odense University Hospital
city: Créteil
country: France
facility: Henri Mondor University Hospital
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Grålum
country: Norway
facility: Ostfold Hospital Trust
city: Oslo
country: Norway
facility: Akershus University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
Study officials:
affiliation: Ostfold Hospital Trust
name: Waleed Ghanima, PhD
role: PRINCIPAL_INVESTIGATOR
References: