The Safety of Repurposing Daratumumab for Relapsed or Refractory Autoimmune Antibody Mediated Hemolytic Anemia

NCT05004259 | Completed Phase 1 DMC

• 1 other identifier: STUDY02000992 21SUL992
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

A single-arm study utilizing a 6 x 4 expansion design using daratumumab SC treatment for patients with refractory Autoimmune Hemolytic Anemia.

Conditions

Hemolytic Anemia

Outcome Measures

Primary Outcomes (2)

• Determine safety of treatment

  Monitor for safety by cataloging any infections, injection site reactions or systemic reactions and any other adverse events that occur during the study period. The investigator will also catalog all adverse events, to monitor for any unpredicted side effects in this new patient population, as judged by the treating provider.

  Up to 10 weeks

• Determine dose-limiting toxicities

  Using a 6 by 4 expansion design in which the study will be stopped if a subject experiences unacceptable toxicity. Unacceptable toxicity is defined as 2 of the first 6 patients experiencing either: Grade 3 or higher infection of any organ system or Grade 3 or higher systemic reactions

  Up to 6 weeks

Secondary Outcomes (2)

• Determine the overall response rate (ORR) of daratumumab in patients with relapsed/refractory AIHA

  Up to 18 weeks

• Determine the time to next treatment (TTNT)

  Through study completion, an average of 1 year

Other Outcomes (2)

• Trough Plasma Concentration (Cmin)

  Pre-treatment through 28 days after the last dose of study treatment

• Assess the change or elimination of anti-Red Blood Cell (RBC) antibody production

  Up to 6 weeks

Study Arms (1)

Arm 1

EXPERIMENTAL

Six weekly doses of subcutaneous daratumumab 1,800mg and hyaluronidase 30,000U.

Drug: Daratumumab / Hyaluronidase Injection

Interventions

Daratumumab / Hyaluronidase Injection DRUG

Subcutaneous injection of daratumumab and hyaluronidase

Arm 1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients must have confirmed autoimmune hemolytic anemia, based on a Hemoglobin \<10 g/dL, a positive Direct Antiglobulin Test, elevated LDH, and elevated Reticulocyte count, low Haptoglobin test.
• Patients must have been previously treated with both a course of steroids starting at a dose of at least 1mg/kg of Prednisone (or steroid equivalent) and at least 100mg of rituximab previously. They must show signs of ongoing hemolysis (as above) either 1) recurring after previous treatment, 2) or while on a Prednisone dose (or equivalent) of 10mg daily or greater.
• Age ≥18 years
• Patients are allowed to be on steroids, as per standard of care. The dosing regimens may include up to 1mg/kg of Prednisone followed by a Prednisone taper, or a regimen of 40mg of Dexamathasone for 4 days. (See Section 6.13 for recommended steroid taper.)
• All patients must give informed consent indicating they are aware of the investigational nature of this treatment, as well as the study protocols and requirements.
• Patients with Evan's syndrome are permissible
• Patients must have performance status of ECOG 0-2

You may not qualify if:

• Patients with active HIV, Hepatitis B, Hepatitis C. We define active as having a detectable viral load. Patients with a prior exposure or well controlled disease while on treatment will be permitted. More information regarding management of these infections can be found in the footnote of the schema in Section 6.1.
• Patients with active Systemic Lupus Erythematosus with other systemic organ involvement requiring treatment
• Patients with active lymphoid malignancy, other than Chronic Lymphoid Leukemia or other low grade lymphoproliferative disorders, not otherwise requiring treatment. Patients with a history of solid tumors are allowed, but must not have received treatment (chemotherapy, surgery, etc.) for a malignancy within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion), which is considered cured with minimal risk of recurrence within 3 years.
• Patients with a serious uncontrolled medical disorder or active infection which would impair their ability to receive study treatment will be excluded. Significant cardiac disease, including uncontrolled high blood pressure, unstable angina, congestive heart failure, myocardial infarction within the previous 3 months or serious cardiac arrhythmias will be excluded. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol will be excluded.
• Patients who are pregnant or breastfeeding
• COPD with an FEV1 \<50% predicted, or moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification
• Renal failure with GFR \<20 ml/min
• End stage liver disease, as defined by local guidelinesEnd stage liver disease, as defined by local guidelines
• Prior treatment with daratumumab or any other anti-CD38 therapies
• Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer.

Sponsors & Collaborators

• Dartmouth-Hitchcock Medical Center: lead

Study Sites (1)

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

Related Publications (13)

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  PMID: 17582741 BACKGROUND

• Lechner K, Jager U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010 Sep 16;116(11):1831-8. doi: 10.1182/blood-2010-03-259325. Epub 2010 Jun 14.

  PMID: 20548093 BACKGROUND

• Birgens H, Frederiksen H, Hasselbalch HC, Rasmussen IH, Nielsen OJ, Kjeldsen L, Larsen H, Mourits-Andersen T, Plesner T, Ronnov-Jessen D, Vestergaard H, Klausen TW, Schollkopf C. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol. 2013 Nov;163(3):393-9. doi: 10.1111/bjh.12541. Epub 2013 Aug 24.

  PMID: 23981017 BACKGROUND

• Reynaud Q, Durieu I, Dutertre M, Ledochowski S, Durupt S, Michallet AS, Vital-Durand D, Lega JC. Efficacy and safety of rituximab in auto-immune hemolytic anemia: A meta-analysis of 21 studies. Autoimmun Rev. 2015 Apr;14(4):304-13. doi: 10.1016/j.autrev.2014.11.014. Epub 2014 Dec 9.

  PMID: 25497766 BACKGROUND

• Zanella A, Barcellini W. Treatment of autoimmune hemolytic anemias. Haematologica. 2014 Oct;99(10):1547-54. doi: 10.3324/haematol.2014.114561.

  PMID: 25271314 BACKGROUND

• Schuetz C, Hoenig M, Moshous D, Weinstock C, Castelle M, Bendavid M, Shimano K, Tolbert V, Schulz AS, Dvorak CC. Daratumumab in life-threatening autoimmune hemolytic anemia following hematopoietic stem cell transplantation. Blood Adv. 2018 Oct 9;2(19):2550-2553. doi: 10.1182/bloodadvances.2018020883.

  PMID: 30291113 BACKGROUND

• Even-Or E, Naser Eddin A, Shadur B, Dinur Schejter Y, Najajreh M, Zelig O, Zaidman I, Stepensky P. Successful treatment with daratumumab for post-HSCT refractory hemolytic anemia. Pediatr Blood Cancer. 2020 Jan;67(1):e28010. doi: 10.1002/pbc.28010. Epub 2019 Sep 22.

  PMID: 31544339 BACKGROUND

• Tolbert, Vanessa P., et al.

  BACKGROUND

• Migdady Y, Ediriwickrema A, Jackson RP, Kadi W, Gupta R, Socola F, Arai S, Martin BA. Successful treatment of thrombocytopenia with daratumumab after allogeneic transplant: a case report and literature review. Blood Adv. 2020 Mar 10;4(5):815-818. doi: 10.1182/bloodadvances.2019001215.

  PMID: 32119735 BACKGROUND

• Blennerhassett R, Sudini L, Gottlieb D, Bhattacharyya A. Post-allogeneic transplant Evans syndrome successfully treated with daratumumab. Br J Haematol. 2019 Oct;187(2):e48-e51. doi: 10.1111/bjh.16171. Epub 2019 Aug 23. No abstract available.

  PMID: 31441030 BACKGROUND

• Hill QA, Hill A, Berentsen S. Defining autoimmune hemolytic anemia: a systematic review of the terminology used for diagnosis and treatment. Blood Adv. 2019 Jun 25;3(12):1897-1906. doi: 10.1182/bloodadvances.2019000036.

  PMID: 31235526 BACKGROUND

• Chapuy CI, Aguad MD, Nicholson RT, AuBuchon JP, Cohn CS, Delaney M, Fung MK, Unger M, Doshi P, Murphy MF, Dumont LJ, Kaufman RM; DARA-DTT Study Group* for the BEST Collaborative. International validation of a dithiothreitol (DTT)-based method to resolve the daratumumab interference with blood compatibility testing. Transfusion. 2016 Dec;56(12):2964-2972. doi: 10.1111/trf.13789. Epub 2016 Sep 7.

  PMID: 27600566 BACKGROUND

• Go RS, Winters JL, Kay NE. How I treat autoimmune hemolytic anemia. Blood. 2017 Jun 1;129(22):2971-2979. doi: 10.1182/blood-2016-11-693689. Epub 2017 Mar 30.

  PMID: 28360039 BACKGROUND

MeSH Terms

Conditions

Anemia, Hemolytic

Interventions

daratumumab; Hyaluronoglucosaminidase

Condition Hierarchy (Ancestors)

Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Glycoside Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Polysaccharide-Lyases; Carbon-Oxygen Lyases; Lyases

Study Officials

• Matthew Sullivan, MD

  Dartmouth-Hitchcock Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine, Geisel School of Medicine, Dartmouth

Study Record Dates

• First Submitted: July 28, 2021
• First Posted: August 13, 2021
• Study Start: March 21, 2022
• Primary Completion: September 21, 2024
• Study Completion: September 21, 2024
• Last Updated: March 30, 2025

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)