NEXI-001 + Decitabine for AML or MDS

Overseen By Monzr M. Al Malki, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: GVHD, Cardiovascular disease, Autoimmune, others

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

Compensation: Varies

Number of Visits: 4

Duration: 33-38 days per cycle

31 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects and best dose of NEXI-001 when given with decitabine and lymphodepleting chemotherapy in treating patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory) following an allogeneic hematopoietic cell transplantation from a matched donor. NEXI-001 is a type of chimeric antigen receptor T cell therapy in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Lymphodepleting chemotherapy, with fludarabine and cyclophosphamide, helps kill cancer cells in the body and helps prepare the body for the new CAR-T cells. Giving NEXI-001 with decitabine and lymphodepleting chemotherapy may be safe and tolerable in treating patients with relapsed or refractory AML or MDS following an allogeneic hematopoietic cell transplantation from a matched donor.

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

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that patients receiving systemic corticosteroids or other immunosuppressant agents at the time of initiation of chemotherapy are excluded, so you may need to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Decitabine for treating AML or MDS?

Decitabine has been shown to improve survival and response rates in patients with acute myeloid leukemia (AML) and has induced positive blood and bone marrow responses in patients with advanced myelodysplastic syndromes (MDS). It is generally well tolerated and offers a valuable treatment option for patients who are not eligible for more intensive therapies. ^{1 2 3 4 5}

Is the treatment with Decitabine safe for humans?

Decitabine has been studied for safety in patients with conditions like acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In these studies, some patients experienced serious side effects like cerebral infarction (a type of stroke), subdural hematoma (bleeding in the brain), and pulmonary hypertension (high blood pressure in the lungs). However, it was generally well tolerated and considered safe for many patients. ^{1 6 7 8 9}

How is the drug NEXI-001 + Decitabine different from other treatments for AML or MDS?

NEXI-001 + Decitabine is unique because it combines a novel therapy, NEXI-001, with Decitabine, a hypomethylating agent that reactivates silenced tumor suppressor genes. This combination may offer a new approach for patients with AML or MDS, especially those who are not eligible for standard chemotherapy. ^{1 2 7 10 11}

Research Team

Monzr M. Al Malki

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) that has returned after treatment or hasn't responded to previous treatments, and who have had a matched donor stem cell transplant. Specific eligibility details are not provided.

Inclusion Criteria

I am mostly able to care for myself and carry out daily activities.

I had a stem cell transplant from a donor over 100 days ago.

Documented informed consent of the participant and/or legally authorized representative and documented informed consent of the donor

Exclusion Criteria

The donor I have has an ongoing infection that isn't getting better with treatment.

Known hypersensitivity to any component of the NEXI-001 T-cell product or specific medications

I have not received a live virus vaccine in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive decitabine and lymphodepleting chemotherapy followed by NEXI-001 T cell infusions

33-38 days per cycle

Multiple visits for infusions and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Every 3 months

Extension

Patients may receive an additional cycle of treatment if criteria are met

33-38 days per additional cycle

Treatment Details

Interventions

• Decitabine
• Fludarabine and Cyclophosphamide
• NEXI-001

Trial Overview The trial tests the safety and optimal dose of NEXI-001, a CAR T-cell therapy, combined with decitabine and lymphodepleting chemotherapy using fludarabine and cyclophosphamide in patients with relapsed/refractory AML or MDS post-transplant.

Participant Groups

Group I: Treatment (NEXI-001, decitabine, chemotherapy) Experimental Treatment 12 Interventions

DONOR: Donors undergo leukapheresis on study. PATIENTS: Patients may receive bridging therapy per standard of care ≥ 14 days prior to the start of cycle 1. Patients receive decitabine IV over 1 hour QD on day -3, -5 or -10 to day -1, lymphodepletion chemotherapy with fludarabine IV over 30 minutes QD and cyclophosphamide IV over 60 minutes QD on day -5 to -3 and then receive NEXI-001 IV over 30 minutes QD on days 1, 8 and 15 of cycle 1. Cycles repeat every 33 or 38 days in the absence of disease progression or unacceptable toxicity. If NEXI-001 cells remain and treatment criteria are met, patients may receive and additional cycle of decitabine IV over 1 hour QD on day -5 to -1 and NEXI-001 IV QD on days 1, 8 and 15 in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO during screening, bone marrow aspirate and/or bone marrow biopsy, PET/ CT scan or MRI and blood sample collection throughout the study.

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

Decitabine is an effective hypomethylating agent for treating acute myeloid leukemia (AML), significantly improving overall survival and response rates compared to standard care, based on results from the phase 3 DACO-016 trial with adult patients who are not eligible for standard chemotherapy.

The treatment is generally well tolerated and remains effective even in patients with adverse-risk karyotypes or TP53 mutations, making it a valuable option for those unfit for more intensive therapies, with potential for future combination treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. Santini, V., Lübbert, M., Wierzbowska, A., et al.[2022]

In a study of 44 patients with relapsed/refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), the combination of decitabine with the EIAG regimen resulted in a higher modified composite complete response (mCRc) rate of 72.7% compared to 40.9% in the CAG regimen group, indicating improved efficacy.

Both treatment regimens led to significant myelosuppression as a common adverse effect, but there was no increase in non-hematological toxicities, suggesting that decitabine combined with EIAG is a safe option that enhances remission rates without adding extra risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified EIAG Regimen in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome]. Mao, JP., Xue, LG., Zhu, YX., et al.[2023]

In a study of 79 patients with acute myeloid leukemia and myelodysplastic syndromes, decitabine alone or in combination with CAG chemotherapy showed high overall response rates (ORR) of 53.3% to 69.2%, indicating its efficacy in treating these conditions.

All treatment groups tolerated decitabine well, with no treatment-related deaths reported, although there were significant adverse events such as infections and hematological toxicities, which were managed with supportive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The clinical efficacy of the patients of acute myeloid leukemia and myelodysplastic syndromes treated with decitabine alone, combined with half or one couse of CAG regimen]. Gao, S., Qiu, H., Jin, Z., et al.[2018]

In a phase I/II study involving 37 patients with myelodysplastic syndrome (MDS), decitabine was found to be safe, with manageable side effects, and showed efficacy with a complete response rate of 20.6% at a dosage of 20 mg/m².

The treatment led to significant hypomethylation in myeloid cells, which may contribute to its therapeutic effects, and resulted in a median duration of remission of over 474 days, with a 2-year acute myeloid leukemia-free survival rate of 52%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II study of decitabine in patients with myelodysplastic syndrome: a multi-center study in Japan. Oki, Y., Kondo, Y., Yamamoto, K., et al.[2021]

Decitabine, a hypomethylating agent, has been shown to improve outcomes in patients with myelodysplastic syndromes (MDS), achieving a 17% overall response rate and 9% complete remissions in a Phase III trial compared to best supportive care.

In high-risk MDS patients, decitabine significantly prolonged the time to transformation to acute myelogenous leukemia or death, indicating its potential to alter the disease's natural history.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of decitabine in the treatment of myelodysplastic syndromes. Atallah, E., Kantarjian, H., Garcia-Manero, G.[2019]

This case study reports the successful use of decitabine and lenalidomide in treating a patient with myelodysplastic syndrome (MDS) characterized by a 5q deletion and elevated blast counts, leading to significant improvements in hemoglobin levels and cessation of transfusion dependency after just two cycles.

The treatment combination was well-tolerated with no notable side effects, suggesting it could be a promising option for MDS patients with similar profiles, although further validation in larger studies is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide Plus Decitabine Treatment in a Myelodysplastic Syndrome Patient With Deletion 5q and Excess Blasts. Serin, I., Eren, R., Dogu, MH.[2020]

References

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

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. [2022]

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

5-Aza-2'-deoxycytidine (Decitabine) induces trilineage response in unfavourable myelodysplastic syndromes. [2018]

3. China pubmed.ncbi.nlm.nih.gov

[Analysis of Decitabine Therapeutic Effeicacy for Patients with Relapsed MDS/AML and High-Risk AML Patients after HSCT]. [2020]

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

Decitabine-Containing Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Intermediate- and High-Risk Myelodysplastic Syndrome/Acute Myeloid Leukemia: Potential Decrease in the Incidence of Acute Graft versus Host Disease. [2022]

5. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Modified EIAG Regimen in the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome]. [2023]

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

[The clinical efficacy of the patients of acute myeloid leukemia and myelodysplastic syndromes treated with decitabine alone, combined with half or one couse of CAG regimen]. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Phase I/II study of decitabine in patients with myelodysplastic syndrome: a multi-center study in Japan. [2021]

8. China pubmed.ncbi.nlm.nih.gov

[The clinical safety and efficacy of low dose subcutaneous decitabine in treating acute myeloid leukemia and intermediate- or higer-risk myelodysplastic syndromes in the elderly patients]. [2019]

9. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Different Dosages of Decitabine in the Treatment of High-Risk Patients with Myelodysplastic Syndrome]. [2021]

10. England pubmed.ncbi.nlm.nih.gov

The role of decitabine in the treatment of myelodysplastic syndromes. [2019]

11. Canada pubmed.ncbi.nlm.nih.gov

Lenalidomide Plus Decitabine Treatment in a Myelodysplastic Syndrome Patient With Deletion 5q and Excess Blasts. [2020]