Stem Cell Transplant Conditioning for Blood Cancers

(ADAPT Trial)

Overseen By University of California Irvine Medical

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, Irvine

Disqualifiers: Pregnancy, Active infection, CNS disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to prepare patients with certain blood cancers for stem cell transplants. It uses a combination of medications, including the chemotherapy drugs Fludarabine and Melphalan, along with Total Body Irradiation, to help the body accept new stem cells. The trial seeks participants diagnosed with blood cancers such as AML, ALL, or CLL who require a stem cell transplant. Eligible participants should have had these conditions long enough to need a transplant and must have a matching donor. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of fludarabine, melphalan, and total body irradiation (TBI) in stem cell transplants is generally well-tolerated. One study found that this treatment had a good safety record, with non-cancer-related death rates at about 10% to 15%. Severe acute graft-versus-host disease (where donor cells attack the recipient's body) occurred in about 10% of cases, with long-term cases being similar.

Another study indicated that using fludarabine and TBI, even with imperfectly matched donors, was well-tolerated, meaning the side effects were manageable. This suggests that while risks exist, the treatment has been safe enough for continued use in clinical settings. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about this treatment for blood cancers because it uses a combination of fludarabine, melphalan, and total body irradiation (TBI) to prepare patients for a stem cell transplant. Unlike traditional chemotherapy, which relies heavily on high-dose drugs alone, this approach tailors the conditioning regimen based on individual risk factors like the patient's age and performance status. This personalized method aims to optimize effectiveness while potentially reducing side effects. Additionally, using TBI as part of the conditioning can more effectively target cancer cells throughout the entire body, offering hope for improved outcomes compared to standard chemotherapy-based protocols.

What evidence suggests that this trial's treatments could be effective for blood cancers?

In this trial, participants will receive a combination of fludarabine, melphalan, and total body irradiation (TBI) as part of the conditioning regimen for allogeneic stem cell transplantation. Research has shown that this combination can help donor stem cells successfully engraft in patients with blood cancers and can prevent cancer recurrence for an extended period. The treatment plan is adaptable, allowing dose adjustments based on each participant's needs, enhancing its effectiveness. While TBI alone may not always improve outcomes, its use with fludarabine and melphalan has succeeded in adults requiring a stem cell transplant. Overall, this method appears promising for treating blood cancers like AML, ALL, and others. ^{1 6 7 8 9}

Who Is on the Research Team?

Stefan O Ciurea, MD

Principal Investigator

Chao Family Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Fludarabine
• Melphalan
• Total Body Irradiation

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.

How Is the Trial Designed?

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 European Union, United States, Canada for the following indications:

Approved in European Union as Fludara for:

• Chronic lymphocytic leukemia
• Mantle-cell lymphoma
• Non-Hodgkin's lymphoma

Approved in United States as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Stem Cell Transplant Conditioning

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03494569?term=CB-3025&rank=9

Total Marrow and Lymphoid Irradiation, Fludarabine, and ... This phase I studies the side effects and best dose of total marrow and lymphoid irradiation when given together with fludarabine and melphalan before donor ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/16435013/

Total body irradiation, fludarabine, melphalan, and ... The regimen of TBI, fludarabine, and melphalan allows the engraftment of allogeneic hematopoietic stem cells (including mismatched CB). It was fairly well ...

3. ashpublications.org ashpublications.org/blood/article/104/11/1827/90330/Total-Body-Irradiation-TBI-Fludarabine-F-Melphalan

Total Body Irradiation (TBI), Fludarabine (F), Melphalan (M ... Abstract. The FM reduced-intensity preparative regimen has been used successfully in adults for allogeneic HSCT.

4. sciencedirect.com sciencedirect.com/science/article/pii/S2666636721008915

Outcomes of Fludarabine, Melphalan and Total Body ... Our study shows that Flu-Mel140-TBI seems feasible and provides durable disease control. Addition of TBI did not appear to improve outcomes.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT00856388

Fludarabine Phosphate, Melphalan, Total-Body Irradiation ... This clinical trial is studying how well giving fludarabine phosphate and melphalan together with total-body irradiation followed by donor stem cell ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33991722/

Outcomes of Fludarabine, Melphalan and Total Body ... We retrospectively evaluated outcomes of patients receiving Flu-Mel140-TBI followed by HLA-matched donor allogeneic hematopoietic stem cell ...

7. astctjournal.org astctjournal.org/article/S1083-8791(17)30761-9/fulltext

Total Marrow Lymphoid Irradiation/Fludarabine/ Melphalan ... Highlights. •. Focused radiation is a potential strategy to augment reduced-intensity conditioning for allogeneic stem cell transplantation.

8. sciencedirect.com sciencedirect.com/science/article/pii/S2666636724005852

Total Body Irradiation and Fludarabine with Post- ... Total body irradiation- and fludarabine-based myeloablative conditioning regimen was well tolerated in mismatched related and unrelated donor HCT recipients.

9. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.27738

Phase II Trial of Reduced‐Intensity Fludarabine, Melphalan ... Though this regimen yields favorable toxicity including rates of non- relapse mortality (NRM) ~10%–15%, severe acute GVHD ~10%, and chronic GVHD ...