Targeted Immunotherapy for Leukemia

(ALLO-T-DART Trial)

Recruiting at 16 trial locations

Overseen By Erin Morris, RN

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: New York Medical College

Disqualifiers: HIV, Hepatitis B, Hepatitis C, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 21

30 Participants Needed

Trial Summary

What is the purpose of this trial?

A Phase I trial to determine the safety of targeted immunotherapy with daratumumab (DARA) IV after total body irradiation (TBI)-based myeloablative conditioning and allogeneic hematopoietic cell transplantation (HCT) for children, adolescents, and young adults (CAYA) with high risk T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LLy). Pre- and post-HCT NGS-MRD studies will be correlated with outcomes in children, adolescents, and young adults with T-ALL undergoing allogeneic HCT and post-HCT DARA treatment. The study will also evaluate T-cell repertoire and immune reconstitution prior to and following DARA post-HCT treatment and correlate with patient outcomes.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Daratumumab for leukemia?

Research shows that Daratumumab, which targets a protein called CD38, has been effective in treating T-cell acute lymphoblastic leukemia (T-ALL) in preclinical studies and has shown promising results in a patient with a specific type of leukemia called Early Thymic Precursor acute lymphoblastic leukemia (ETP-ALL). Additionally, Daratumumab has been approved for use in multiple myeloma, another type of blood cancer, where it has shown significant effectiveness. ^{1 2 3 4 5}

Is targeted immunotherapy for leukemia, such as Daratumumab, generally safe for humans?

Daratumumab, also known as Darzalex, has been studied for safety in humans, and while specific safety data for leukemia is not provided, similar treatments have shown manageable side effects. Common side effects for antibody-drug conjugates include fatigue, nausea, and diarrhea, with some risk of more serious issues like arrhythmias (irregular heartbeats) and lung problems. Overall, these treatments are considered to have a favorable safety profile with proper monitoring and management. ^{6 7 8 9 10}

How does the drug used in targeted immunotherapy for leukemia differ from other treatments?

The drug used in targeted immunotherapy for leukemia, daratumumab, is unique because it is a monoclonal antibody that specifically targets the CD38 protein on cancer cells, which is not a common target in standard leukemia treatments. This approach is novel as it uses the body's immune system to attack cancer cells, offering a different mechanism of action compared to traditional chemotherapy. ^{1 2 11 12 13}

Research Team

Allyson Flower, MD

Principal Investigator

New York Medical College

Mitchell Cairo, MD

Principal Investigator

New York Medical College

Troy Quigg, DO

Principal Investigator

Helen DeVos Children's Hospital

Eligibility Criteria

This trial is for children, adolescents, and young adults (0-39 years old) with high-risk T-cell acute lymphoblastic leukemia or lymphoma in remission or complete response after therapy. They must be planning a stem cell transplant, have good performance status, recovered from previous treatments' effects, meet organ function criteria, and not be pregnant or breastfeeding.

Inclusion Criteria

My T-cell acute lymphoblastic leukemia is in remission or responded well after more treatment.

I can do most of my daily activities without help.

My organs are functioning well.

Exclusion Criteria

I have asthma.

I have not had a stem cell transplant before.

Seropositive for HIV, hepatitis B or hepatitis C

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Daratumumab (DARA) IV weekly for 8 doses

8 weeks

8 visits (in-person)

Consolidation

Daratumumab (DARA) IV every 2 weeks for 8 doses

16 weeks

8 visits (in-person)

Maintenance

Daratumumab (DARA) IV every 4 weeks until Day +270

approximately 22 weeks

5-6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Daratumumab

Trial Overview The trial tests the safety of daratumumab immunotherapy following total body irradiation and stem cell transplantation in patients with T-cell leukemia/lymphoma. It will also study how this treatment affects disease markers and immune system recovery to see if there's a link to patient outcomes.

Participant Groups

Group I: Interventional Experimental Treatment 1 Intervention

Phase 1: 3 dose levels to determine safety (15 patients) Dose expansion: Daratumumab (DARA) treatment post-HCT 1. Induction: DARA IV weekly x 8 doses (Weeks 1-8) 2. Consolidation: DARA IV every 2 weeks x 8 doses (Weeks 9-24) 3. Maintenance: DARA IV every 4 weeks (Stop at Day +270)

Who Is Running the Clinical Trial?

New York Medical College

Lead Sponsor

Trials

73

Recruited

8,700+

Findings from Research

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]

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]

CD38 is consistently expressed on the blasts of patients with relapsed Early Thymic Precursor acute lymphoblastic leukemia (ETP-ALL), making it a promising target for therapy.

The clinical use of daratumumab, a CD38-targeting treatment, in a patient with relapsed ETP-ALL post-allogeneic transplant showed long-term positive outcomes, with follow-up extending over 3 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long term outcome of a patient with relapsed refractory early thymic precursor acute lymphoblastic leukemia treated with daratumumab. Punatar, S., Gokarn, A., Nayak, L., et al.[2021]

A 26-year-old man with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) that was negative for common immunotherapy targets (CD19, CD20, and CD22) was successfully treated using a combination of venetoclax and daratumumab with chemotherapy.

This case highlights a potential new treatment strategy for patients with R/R B-ALL lacking traditional immunotherapeutic targets, suggesting that targeting Bcl-2 and CD38 may provide effective options in otherwise limited scenarios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab and venetoclax in combination with chemotherapy provide sustained molecular remission in relapsed/refractory CD19, CD20, and CD22 negative acute B lymphoblastic leukemia with KMT2A-AFF1 transcript. Voruz, S., Blum, S., de Leval, L., et al.[2021]

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]

Antibody-drug conjugates (ADCs) are a new class of targeted cancer treatments that combine the tumor-targeting ability of antibodies with the powerful effects of cytotoxic drugs, significantly improving treatment options for certain breast cancer subtypes.

While ADCs generally have favorable safety profiles, they can cause specific adverse reactions such as thrombocytopenia and hepatotoxicity, necessitating careful monitoring and management by healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chinese expert consensus of antibody-drug conjugate toxicity management for breast cancer]. [2022]

In a study of 497 elderly patients with inflammatory bowel disease, those treated with vedolizumab (VDZ) had a lower incidence of mild infections (93.1 per 1000 patient-years) compared to those on 5-aminosalicylic acid (5-ASA) and chronic steroids, suggesting a potentially safer profile for VDZ.

The incidence of malignancies was similar between the VDZ and 5-ASA groups (17.6 vs. 15.6 per 1000 patient-years), while the steroid group had a higher incidence (42.6 per 1000 patient-years), indicating that VDZ may be a safer option for elderly patients with IBD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of Infections and Malignancy Among Elderly Male Patients with IBD Exposed to Vedolizumab, Prednisone, and 5-ASA Medications: A Nationwide Retrospective Cohort Study. Khan, N., Pernes, T., Weiss, A., et al.[2021]

In a phase II study involving 61 patients with relapsed or refractory diffuse large B-cell lymphoma, coltuximab ravtansine showed an overall response rate of 43.9%, indicating moderate efficacy in this difficult-to-treat population.

The treatment was generally well tolerated, with common side effects including fatigue (30%) and nausea (23%), and serious adverse events were relatively low, suggesting a favorable safety profile for this antibody drug conjugate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II multicenter study of the anti-CD19 antibody drug conjugate coltuximab ravtansine (SAR3419) in patients with relapsed or refractory diffuse large B-cell lymphoma previously treated with rituximab-based immunotherapy. Trnĕný, M., Verhoef, G., Dyer, MJ., et al.[2019]

A study analyzing 140 reports of arrhythmias associated with antibody-drug conjugates (ADCs) found that gemtuzumab ozogamicin and brentuximab vedotin were linked to increased arrhythmia risk, with brentuximab vedotin having the highest number of reports (67 cases).

Most arrhythmias occurred within 60 days of treatment, particularly in patients with hematologic tumors and breast cancer, highlighting the need for careful monitoring during this period to enhance patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Caution the arrhythmia association with antibody-drug conjugates: a pharmacovigilance study. Li, X., Chen, G., Hu, Y., et al.[2023]

Fam-trastuzumab deruxtecan-nxki (ENHERTU) received accelerated FDA approval for treating HER2-positive breast cancer in patients who have already undergone two or more anti-HER2 therapies, based on a study involving 184 patients that showed a confirmed overall response rate of 60.3%.

While ENHERTU is effective, it carries significant risks, including severe interstitial lung disease and neutropenia, highlighting the importance of monitoring for serious side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer. Narayan, P., Osgood, CL., Singh, H., et al.[2022]

Daratumumab is a monoclonal antibody that effectively targets CD38 on multiple myeloma cells, leading to cell death through various mechanisms such as complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.

It has shown a favorable safety profile and significant clinical activity as both a standalone treatment and in combination with lenalidomide for patients with relapsed multiple myeloma who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab: monoclonal antibody therapy to treat multiple myeloma. Xia, C., Ribeiro, M., Scott, S., et al.[2018]

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]

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]

References

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

Daratumumab: First Global Approval. [2018]

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

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

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

Long term outcome of a patient with relapsed refractory early thymic precursor acute lymphoblastic leukemia treated with daratumumab. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Daratumumab and venetoclax in combination with chemotherapy provide sustained molecular remission in relapsed/refractory CD19, CD20, and CD22 negative acute B lymphoblastic leukemia with KMT2A-AFF1 transcript. [2021]

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

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

6. China pubmed.ncbi.nlm.nih.gov

[Chinese expert consensus of antibody-drug conjugate toxicity management for breast cancer]. [2022]

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

Incidence of Infections and Malignancy Among Elderly Male Patients with IBD Exposed to Vedolizumab, Prednisone, and 5-ASA Medications: A Nationwide Retrospective Cohort Study. [2021]

8. Italy pubmed.ncbi.nlm.nih.gov

A phase II multicenter study of the anti-CD19 antibody drug conjugate coltuximab ravtansine (SAR3419) in patients with relapsed or refractory diffuse large B-cell lymphoma previously treated with rituximab-based immunotherapy. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Caution the arrhythmia association with antibody-drug conjugates: a pharmacovigilance study. [2023]

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

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer. [2022]

11. Spain pubmed.ncbi.nlm.nih.gov

Daratumumab: monoclonal antibody therapy to treat multiple myeloma. [2018]

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

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

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

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