Stem Cell Transplant Conditioning for Blood Cancers

(ADAPT Trial)

Overseen by Stefan O Ciurea, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of California, Irvine

Disqualifiers: Pregnancy, Active infection, CNS disease, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial involves replacing damaged bone marrow with healthy donor cells in patients who have not improved with other treatments. The process includes preparation with drugs and radiation, followed by the procedure and medications to prevent complications.

Will I have to stop taking my current medications?

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 treatment for blood cancers?

Research shows that the combination of fludarabine, melphalan, and total body irradiation (TBI) can improve survival and disease control in patients undergoing stem cell transplantation for blood cancers. Specifically, the regimen with higher melphalan dose (FluMelTBI-75) was better tolerated and led to improved overall survival and progression-free survival compared to other regimens. ^{1 2 3 4 5}

Is the combination of fludarabine, melphalan, and total body irradiation generally safe for humans?

The combination of fludarabine, melphalan, and total body irradiation has been associated with significant side effects, including heart, kidney, and liver problems, as well as mouth sores and diarrhea. Some studies reported severe heart issues in a few patients, and there were deaths related to the treatment. While it can be effective for some patients, the safety profile shows considerable risks. ^{2 3 4 5 6}

How does the treatment with Fludarabine, Melphalan, and Total Body Irradiation differ from other treatments for blood cancers?

This treatment combines Fludarabine and Melphalan with Total Body Irradiation (TBI) to enhance disease control and reduce toxicity compared to other regimens. The addition of TBI aims to improve survival and disease control, particularly in patients not in complete remission, while being better tolerated than regimens without TBI. ^{1 3 4 7 8}

Research Team

Stefan O Ciurea, MD

Principal Investigator

Chao Family Comprehensive Cancer Center

Eligibility Criteria

Adults aged 18-70 with certain blood cancers like AML, ALL, MDS, and others needing a stem cell transplant can join. They must have a matched donor, good organ function (liver, heart, kidneys), and be able to follow the study plan. Pregnant individuals or those with active infections or CNS diseases cannot participate.

Inclusion Criteria

My major organs are functioning well.

Serum creatinine clearance equal or more than 50 ml/min (calculated with Cockroft-Gault formula)

Diffusing capacity for carbon monoxide (DLCO) equal or greater than 50% predicted corrected for hemoglobin

Exclusion Criteria

I have had brain or eye disease symptoms in the last 3 months.

You currently have a bacterial or viral infection that is not under control. The Principal Investigator (the person in charge of the study) will make the final decision on whether this criterion applies to you.

I have been diagnosed with lymphoma that started in my brain or spinal cord.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants receive a conditioning regimen with fludarabine, melphalan, and total body irradiation (TBI) tailored based on risk factors

1 week

Transplantation

Participants undergo allogeneic stem cell transplantation

1 day

Post-Transplantation

Participants receive post-transplant high dose cyclophosphamide, tacrolimus, and mycophenolate mofetil for graft-versus-host prophylaxis

2-4 weeks

Follow-up

Participants are monitored for safety and efficacy post-transplantation

Up to 2 years

Treatment Details

Interventions

• Fludarabine (Anti-metabolites)
• Melphalan (Alkylating agents)
• Total Body Irradiation (Radiation Therapy)

Trial Overview The trial is testing a new way to prepare patients for stem cell transplants using drugs Fludarabine and Melphalan plus Total Body Irradiation. The doses vary based on each patient's risk factors in this phase II study where everyone gets the same treatment.

Participant Groups

Group I: Patients with AML, ALL, MDS, CML, NHL, HD, CLL requiring AHSCT Experimental Treatment 3 Interventions

Patients will be treated with allogeneic stem cell transplantation (AHSCT) using fludarabine, melphalan and total body irradiation (TBI) conditioning with different melphalan and TBI doses based on their Hematopoietic Cell Transplant - Composite Risk (HCT-CR), age, and Karnofski performance status (KPS).

Fludarabine is already approved in Canada for the following indications:

Approved in Canada as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

University of California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

Chad T. Lefteris

University of California, Irvine

Chief Executive Officer since 2019

MBA from University of California, Irvine

Michael J. Stamos

University of California, Irvine

Chief Medical Officer since 2019

MD, PhD from University of California, Irvine

Findings from Research

In a study of 394 acute myeloid leukemia patients undergoing allogeneic stem cell transplantation, the fludarabine plus melphalan (FM) regimen showed a significantly lower relapse incidence compared to fludarabine plus busulfan (FB), indicating better control of the disease.

Despite the differences in relapse rates, both FM and FB regimens resulted in similar overall survival rates, suggesting that while FM may be more effective in preventing relapse, both treatments are comparably effective in terms of long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Baron, F., Labopin, M., Peniket, A., et al.[2015]

In a study of 31 patients with hematologic malignancies who were poor candidates for total body irradiation (TBI), the fludarabine-melphalan regimen resulted in successful engraftment for all patients, indicating its efficacy in stem cell transplantation.

However, the treatment was associated with significant regimen-related toxicities, including renal, hepatic, and mucosal issues, leading to seven regimen-related deaths, highlighting the need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies. Van Besien, K., Devine, S., Wickrema, A., et al.[2013]

The addition of total body irradiation (TBI) and a reduction in melphalan dosage in the FluMelTBI-75 regimen led to improved overall survival (OS) and progression-free survival (PFS) compared to the standard FluMel regimen, based on a phase II trial involving 94 patients.

FluMelTBI-75 was better tolerated, showing a significant reduction in stomatitis and improved disease control for patients not in complete remission at the time of transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-Intensity Conditioning with Fludarabine, Melphalan, and Total Body Irradiation for Allogeneic Hematopoietic Cell Transplantation: The Effect of Increasing Melphalan Dose on Underlying Disease and Toxicity. Chen, GL., Hahn, T., Wilding, GE., et al.[2022]

The combination of fludarabine and melphalan with total body irradiation (Flu-Mel140-TBI) in 81 patients undergoing allogeneic stem cell transplantation showed a 3-year overall survival rate of 39.81%, indicating that this regimen is feasible and can provide durable disease control.

Despite the addition of TBI, there was no significant improvement in outcomes compared to previous reports of Flu-Mel140 alone, and the study highlighted considerable non-relapse mortality (29.9%) particularly in older patients and those with prior transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Fludarabine, Melphalan and Total Body Irradiation as a Reduced Intensity Conditioning Regimen in Matched Donor Allogeneic Peripheral Blood Stem Cell Transplantation. Modi, D., Chi, J., Kim, S., et al.[2021]

The addition of 9 Gy of total body irradiation (TBI) to a reduced intensity regimen of fludarabine and melphalan in pediatric patients with advanced hematologic malignancies resulted in successful neutrophil and platelet engraftment, with 27 patients achieving neutrophil engraftment by a median of 16 days.

Despite some toxicities like oral mucositis and diarrhea, the treatment was generally well tolerated, and with a median follow-up of 52 months, 7 out of 22 patients with acute lymphoblastic leukemia (ALL) and 5 out of 6 patients with acute myeloid leukemia (AML) remained alive and in remission, indicating potential efficacy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies. Petropoulos, D., Worth, LL., Mullen, CA., et al.[2013]

In a study of 21 patients undergoing non-myeloablative conditioning chemotherapy with melphalan and fludarabine before allogeneic stem cell transplantation, three patients developed severe left ventricular failure, indicating a potential risk of cardiotoxicity with this treatment combination.

This finding is significant as cardiotoxicity from melphalan and fludarabine has not been previously reported, highlighting the need for careful assessment and monitoring of cardiac health in patients receiving this pre-transplant regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute left ventricular failure following melphalan and fludarabine conditioning. Ritchie, DS., Seymour, JF., Roberts, AW., et al.[2013]

In a study of 30 adult patients undergoing allogeneic hematopoietic stem cell transplant, fludarabine combined with full-dose busulfan (FluBu) and fludarabine with melphalan (FluMel) showed similar levels of hematological toxicity, indicating that both regimens are comparably safe.

The timing and duration of severe neutropenia were similar between the two groups, with both regimens resulting in a comparable recovery time for neutrophils and platelets post-transplant, suggesting that FluBu can be an effective alternative to standard reduced intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparable kinetics of myeloablation between fludarabine/full-dose busulfan and fludarabine/melphalan conditioning regimens in allogeneic peripheral blood stem cell transplantation. Chunduri, S., Dobogai, LC., Peace, D., et al.[2013]

A study involving 21 patients undergoing a second or greater allogeneic stem cell transplantation (allo-SCT) found that combining intensity-modulated total marrow irradiation (IM-TMI) with fludarabine and melphalan is feasible, with a recommended dose of 12 Gy for effective treatment.

The 2-year cumulative incidence of relapse was 35%, with a 50% overall survival rate, indicating that while the relapse rate remains a concern, this combination therapy shows promise for improving outcomes in patients with relapsed hematologic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 trial utilizing TMI with fludarabine-melphalan in patients with hematologic malignancies undergoing second allo-SCT. Tran, MC., Hasan, Y., Wang, A., et al.[2023]

References

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

Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. [2015]

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

Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies. [2013]

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

Reduced-Intensity Conditioning with Fludarabine, Melphalan, and Total Body Irradiation for Allogeneic Hematopoietic Cell Transplantation: The Effect of Increasing Melphalan Dose on Underlying Disease and Toxicity. [2022]

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

Outcomes of Fludarabine, Melphalan and Total Body Irradiation as a Reduced Intensity Conditioning Regimen in Matched Donor Allogeneic Peripheral Blood Stem Cell Transplantation. [2021]

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

Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Acute left ventricular failure following melphalan and fludarabine conditioning. [2013]

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

Comparable kinetics of myeloablation between fludarabine/full-dose busulfan and fludarabine/melphalan conditioning regimens in allogeneic peripheral blood stem cell transplantation. [2013]

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

A phase 1 trial utilizing TMI with fludarabine-melphalan in patients with hematologic malignancies undergoing second allo-SCT. [2023]