Daratumumab Combination Therapy for High-Risk Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Investigational agents

Disqualifiers: Prior transplant, Active malignancies, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 100

15 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, it mentions that you should not have received intensive therapy, chemotherapy, or radiotherapy for 2 weeks before starting the study, except for certain low-dose or maintenance chemotherapies.

What data supports the effectiveness of the drug Daratumumab Combination Therapy for High-Risk Leukemia?

Research shows that daratumumab, a key component of the therapy, has been effective in treating various blood cancers, including multiple myeloma and T-cell acute lymphoblastic leukemia (T-ALL), by targeting CD38 on cancer cells. In T-ALL, daratumumab showed significant effectiveness in patient-derived models, suggesting it could be promising for high-risk leukemia. ^{1 2 3 4 5}

Is Daratumumab combination therapy generally safe for humans?

Daratumumab, a monoclonal antibody targeting CD38, has been demonstrated to be safe and effective in patients with refractory multiple myeloma, and it is being explored for other conditions like T-cell acute lymphoblastic leukemia and acute myeloid leukemia. However, it can interfere with blood typing tests, which healthcare professionals are informed about to mitigate risks. ^{1 2 3 6 7}

How is the drug 225Ac-DOTA-Anti-CD38 Daratumumab different from other treatments for high-risk leukemia?

The drug 225Ac-DOTA-Anti-CD38 Daratumumab is unique because it combines daratumumab, an antibody targeting CD38, with a radioactive component (225Ac-DOTA), potentially enhancing its ability to target and kill cancer cells in high-risk leukemia. This combination approach is novel compared to standard treatments that typically do not include a radioactive element. ^{3 8 9 10 11}

What is the purpose of this trial?

This phase I trial tests the safety, side effects, best dose, and effectiveness of 225Ac-DOTA-Anti-CD38 daratumumab monoclonal antibody in combination with fludarabine, melphalan and total marrow and lymphoid irradiation (TMLI) as conditioning treatment for donor stem cell transplant in patients with high-risk acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Radioimmunotherapy is treatment with a radioactive substance that is linked to a monoclonal antibody, such as daratumumab, that will find and attach to cancer cells. Radiation given off by the radioisotope my help kill the cancer cells. Chemotherapy drugs, such as fludarabine and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. TMLI is a targeted form of body radiation that targets marrow, lymph node chains, and the spleen. It is designed to reduce radiation-associated side effects and maximize therapy effect. Actinium Ac 225-DOTA-daratumumab combined with fludarabine, melphalan and TMLI may be safe, tolerable, and/or effective as conditioning treatment for donor stem cell transplant in patients with high-risk AML, ALL, and MDS.

Research Team

Jeffrey Wong

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for patients with high-risk acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) who are candidates for donor stem cell transplant. Specific eligibility criteria were not provided, but typically include factors like age, overall health status, and the specifics of their cancer diagnosis.

Inclusion Criteria

Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy

Pretreatment measured creatinine clearance of ≥ 60 ml/minute

Serum bilirubin ≤ 2.0 mg/dl

Exclusion Criteria

I have had radiation treatment to my lung, liver, or kidney.

I have had radiopharmaceutical therapy before.

Prospective participants unable to comply with all study procedures

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for CT, nuclear scan, SPECT scans, bone marrow biopsy, echocardiography, and blood sample collection

Conditioning Treatment

Participants receive daratumumab, indium In 111-DOTA-daratumumab, and actinium Ac 225-DOTA-daratumumab, followed by TMLI, fludarabine, and melphalan as conditioning for hematopoietic cell transplantation

15 days

Daily visits for IV administration and monitoring

Hematopoietic Cell Transplantation

Participants undergo hematopoietic cell transplantation and receive GVHD prophylaxis

1 day

Inpatient stay for transplantation

Follow-up

Participants are monitored for safety, effectiveness, and adverse events post-transplant

2 years

Twice weekly for the first 100 days, then twice monthly up to 6 months, followed by monthly visits

Treatment Details

Interventions

• 225Ac-DOTA-Anti-CD38 Daratumumab
• Daratumumab
• Fludarabine
• Melphalan
• Total Marrow and Lymphoid Irradiation

Trial Overview The trial tests a new treatment combining 225Ac-DOTA-Anti-CD38 daratumumab monoclonal antibody with chemotherapy drugs fludarabine and melphalan, plus total marrow and lymphoid irradiation (TMLI). It aims to find the safest dose that's also effective as pre-transplant conditioning in high-risk AML, ALL, and MDS patients.

Participant Groups

Group I: Treatment ( Actinium Ac 225-DOTA-Daratumumab) Experimental Treatment 17 Interventions

Patients receive daratumumab IV over 45 minutes followed by indium In 111-DOTA-daratumumab IV over 15 minutes and actinium Ac 225-DOTA-daratumumab IV over \~20-40 minutes on day -15. Patients receive TMLI BID on days -8 to -5, fludarabine IV on days -4 to -2 and melphalan IV on day -2, followed by HCT on day 0. Patients receive GVHD prophylaxis with sirolimus and tacrolimus starting on day -1. Patients also undergo CT during screening, nuclear scan and SPECT scans on study, bone marrow biopsy and aspiration, echocardiography, or MUGA, and blood sample collection during screening and throughout study.

225Ac-DOTA-Anti-CD38 Daratumumab is already approved in European Union, United States for the following indications:

Approved in European Union as Darzalex for:

• Multiple myeloma
• Light chain amyloidosis

Approved in United States as Darzalex for:

• Multiple myeloma
• Light chain amyloidosis

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Patients with T-cell acute lymphoblastic leukemia (T-ALL) show high levels of CD38 on their cancer cells, making it a promising target for immunotherapy.

Daratumumab, an antibody that targets CD38, demonstrated significant efficacy in 14 out of 15 patient-derived xenograft models of T-ALL, suggesting it could be a safe and effective treatment option for pediatric patients with this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia. Bride, KL., Vincent, TL., Im, SY., et al.[2021]

ATRA (all-trans retinoic acid) can enhance CD38 expression on acute myeloid leukemia (AML) cells, making them more susceptible to treatment with the anti-CD38 antibody daratumumab (DARA).

The combination of ATRA and DARA not only showed increased cytotoxicity against AML cells in laboratory tests but also led to reduced tumor volume and improved survival rates in mouse models of AML, suggesting a potential new treatment strategy for non-APL forms of AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-leukemic effects of all-trans retinoic acid in combination with Daratumumab in acute myeloid leukemia. Buteyn, NJ., Fatehchand, K., Santhanam, R., et al.[2022]

Daratumumab, an anti-CD38 antibody, shows strong anti-tumor activity in various types of non-Hodgkin lymphoma (NHL), including mantle cell lymphoma (MCL) and follicular lymphoma (FL), both in laboratory models and in vivo, effectively preventing tumor growth and improving overall survival.

The drug enhances the effectiveness of standard chemotherapy regimens (CHOP and R-CHOP) in treating MCL and FL, demonstrating its potential as a valuable addition to existing therapies for these lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab displays in vitro and in vivo anti-tumor activity in models of B-cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens. Vidal-Crespo, A., Matas-Céspedes, A., Rodriguez, V., et al.[2022]

In a small study of five patients with relapsed acute lymphoblastic leukemia (ALL), daratumumab treatment led to complete remission in three out of four T-ALL patients, highlighting its potential efficacy in this context.

Monitoring leukemia burden after daratumumab treatment is crucial, as some leukemic cells may not express CD38, which could lead to misclassification of the disease; using alternative antibodies can help ensure accurate detection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD38: A target in relapsed/refractory acute lymphoblastic leukemia-Limitations in treatment and diagnostics. Vakrmanová, B., Nováková, M., Říha, P., et al.[2022]

A 70-year-old patient with advanced multiple myeloma, who had previously undergone five lines of therapy, achieved a stringent complete response and over 3.5 years of remission with daratumumab monotherapy, significantly exceeding the median response duration of 7.6 months for similar patients.

The patient's treatment with daratumumab led to notable changes in his immune profile, including expansion of CD8+ T-cells and a decrease in regulatory T-cells, indicating a strong adaptive immune response that supports the drug's immunomodulatory effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep sustained response to daratumumab monotherapy associated with T-cell expansion in triple refractory myeloma. Usmani, SZ., Khan, I., Chiu, C., et al.[2022]

A survey of 408 healthcare professionals and blood transfusion management personnel across 12 European countries showed that they were generally aware of the risks associated with daratumumab treatment, particularly its interference with blood typing tests.

While 80% of respondents correctly answered three out of four key questions regarding daratumumab, only 60% identified the specific blood tests affected, indicating a need for improved clarity in educational materials, especially in translations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Healthcare Professionals' Knowledge and Understanding of the Risk of Blood Typing Interference with Daratumumab: A Survey of 12 European Countries. Rosé, M., Bourahla, I., Ghiddi, A., et al.[2021]

Daratumumab administered subcutaneously (SC) significantly reduces the time healthcare providers spend on drug preparation and administration compared to intravenous (IV) administration, with a 63.8% reduction in active HCP time for first treatments.

The SC formulation also drastically decreases patient chair time by 97%, making the treatment process more efficient and potentially increasing patient access to care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a Time and Motion Survey Regarding Subcutaneous versus Intravenous Administration of Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma. Slavcev, M., Spinelli, A., Absalon, E., et al.[2022]

Intravenous daratumumab, when combined with bortezomib, melphalan, and prednisone, significantly improves progression-free survival in patients with newly diagnosed multiple myeloma who cannot undergo autologous stem cell transplantation, as shown in the phase 3 ALCYONE trial.

The addition of daratumumab does not increase overall toxicity compared to the standard treatment, although it may lead to more infusion-related reactions and infections, making it a promising and relatively safe treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Combination Therapy for Transplant-Ineligible Newly Diagnosed Multiple Myeloma. Syed, YY.[2021]

Intravenous daratumumab, when combined with bortezomib, thalidomide, and dexamethasone, significantly improves treatment outcomes for adults with newly diagnosed multiple myeloma, leading to higher rates of stringent complete response and prolonged progression-free survival, as shown in the phase III CASSIOPEIA trial.

The addition of daratumumab has a minimal impact on overall toxicity, with the most common serious side effects being blood-related issues, indicating it is a relatively safe option for patients undergoing treatment for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Combination Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma. Lamb, YN.[2021]

Daratumumab, a monoclonal antibody targeting CD38, has shown significant efficacy as a monotherapy in relapsed/refractory multiple myeloma, achieving an overall response in about one-third of patients, with rapid and durable effects.

In combination with other treatments like bortezomib or lenalidomide, daratumumab significantly prolonged progression-free survival, although the overall survival benefit is still being evaluated, and it was generally well tolerated with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Relapsed and/or Refractory Multiple Myeloma. Blair, HA.[2018]

Daratumumab, a monoclonal antibody targeting CD38, has been approved in the USA for treating multiple myeloma in patients who have undergone at least three prior therapies, demonstrating its role as a treatment option for difficult-to-treat cases.

In a phase II trial, daratumumab monotherapy showed an overall response rate of about 30% in patients with relapsed or refractory multiple myeloma, indicating its efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: First Global Approval. McKeage, K.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Anti-leukemic effects of all-trans retinoic acid in combination with Daratumumab in acute myeloid leukemia. [2022]

3. Italy pubmed.ncbi.nlm.nih.gov

Daratumumab displays in vitro and in vivo anti-tumor activity in models of B-cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

CD38: A target in relapsed/refractory acute lymphoblastic leukemia-Limitations in treatment and diagnostics. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Deep sustained response to daratumumab monotherapy associated with T-cell expansion in triple refractory myeloma. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Assessment of Healthcare Professionals' Knowledge and Understanding of the Risk of Blood Typing Interference with Daratumumab: A Survey of 12 European Countries. [2021]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Results of a Time and Motion Survey Regarding Subcutaneous versus Intravenous Administration of Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Combination Therapy for Transplant-Ineligible Newly Diagnosed Multiple Myeloma. [2021]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Combination Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma. [2021]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Daratumumab: A Review in Relapsed and/or Refractory Multiple Myeloma. [2018]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Daratumumab: First Global Approval. [2018]