Intensity Modulated Total Marrow Irradiation + Fludarabine Phosphate + Melphalan for Hematologic Cancers

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Chicago

Disqualifiers: HIV, Pregnancy, Hepatitis, Cirrhosis, others

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

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the best dose and examine the side effects of a new treatment combination for blood cancer patients whose cancer has returned after initial improvement. The treatment combines a special type of radiation therapy called intensity modulated total marrow irradiation (IMTMI) with the chemotherapy drugs fludarabine phosphate and melphalan. This approach may help prepare the body to accept a donor stem cell transplant by targeting both cancer and healthy bone marrow cells, potentially reducing the chance of cancer returning. Eligible patients include those with conditions like acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) who are undergoing a second stem cell transplant due to cancer relapse. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

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

What prior data suggests that intensity modulated total marrow irradiation is safe for treating hematologic cancers?

A previous study found that intensity modulated total marrow irradiation (IMTMI) was safe and workable for patients with blood cancers, yielding good clinical results. Research has shown that fludarabine phosphate, another treatment in this study, is generally safe but can cause side effects like low white blood cell counts. Melphalan, commonly used in cancer treatment, has also demonstrated safety. Overall, these treatments have shown promising safety results in past studies. This current trial aims to further explore their safety when used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of intensity modulated total marrow irradiation (IMTMI), fludarabine phosphate, and melphalan for treating hematologic cancers because it offers a targeted approach that may reduce side effects compared to traditional total body irradiation. Unlike standard treatments that often involve broader radiation exposure, IMTMI precisely targets the bone marrow, potentially sparing other organs from unnecessary radiation. This precision, combined with the chemotherapy agents fludarabine phosphate and melphalan, aims to enhance cancer cell eradication while minimizing harm to healthy tissues. Moreover, this approach is integrated with protective measures against graft-versus-host disease, using established medications like tacrolimus and mycophenolate mofetil, which adds to its promise in improving patient outcomes.

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

In this trial, participants will receive a combination of treatments, including intensity modulated total marrow irradiation (IMTMI), fludarabine phosphate, and melphalan, to prepare for a stem cell transplant. Research has shown that IMTMI can target radiation to the bone marrow while reducing exposure to healthy organs, potentially lowering the risk of cancer recurrence. Studies have found that fludarabine phosphate works well for some blood cancers, like chronic lymphocytic leukemia, though it can sometimes cause serious side effects. Melphalan has been shown to help patients with multiple myeloma, a type of blood cancer, live longer. Together, these treatments aim to stop cancer cells from growing and help prepare patients for a successful stem cell transplant. ^{6 7 8 9 10}

Who Is on the Research Team?

Hongtao Liu, MD, PhD

Principal Investigator

University of Chicago Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with relapsed blood cancers like AML or high-risk MDS, who are undergoing a second stem cell transplant. They should have good kidney and liver function, not be pregnant, HIV-negative, and have a Karnofsky performance status of 70+. The donor can be the same as the first transplant or a different matched donor.

Inclusion Criteria

Life expectancy is not severely limited by concomitant illness

Human immunodeficiency virus (HIV)-negative

Serum creatinine =<1.5 mg/dL or creatinine clearance > 50 ml/min; some patients with minor deviations may be accepted on protocol after discussion with the principal investigator (PI)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Regimen

Participants receive fludarabine phosphate IV over 30 minutes daily on days -7 to -3 and melphalan IV on day -2. They also undergo IMTMI twice daily for 2 to 5 days between days -7 to -3.

1 week

Transplant

Participants undergo allogeneic peripheral blood stem cell transplant (PBSCT) or bone marrow transplant (BMT) on day 0.

1 day

GVHD Prophylaxis

Participants receive tacrolimus IV continuously over 24 hours or orally BID on days -2 to 180 with taper thereafter and mycophenolate mofetil IV every 8 hours or PO on days 0-28 (for matched donors) or days 0-40 (for alternative donors) with taper to day 60.

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Fludarabine Phosphate
• Intensity Modulated Total Marrow Irradiation
• Melphalan

Trial Overview The trial tests intensity modulated total marrow irradiation (IMTMI) combined with fludarabine phosphate and melphalan before a second stem cell transplant. It aims to see how well this approach works in stopping cancer growth and preventing immune rejection of the new stem cells.

How Is the Trial Designed?

Group I: Treatment (IMTMI, combination chemotherapy, PBSCT or BMT) Experimental Treatment 10 Interventions

CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes daily on days -7 to -3 and melphalan IV on day -2. Patients also undergo IMTMI BID for 2 to 5 days between days -7 to -3. TRANSPLANT: Patients undergo allogeneic PBSCT or BMT on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously over 24 hours or PO BID on days -2 to 180 with taper thereafter and mycophenolate mofetil IV every 8 hours or PO on days 0-28 (for matched donors) or days 0-40 (for alternative donors) with taper to day 60.

Fludarabine Phosphate is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Acute myeloid leukemia

Approved in European Union as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Acute myeloid leukemia

Approved in Canada as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Acute myeloid leukemia

Approved in Japan as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

Fludara I.V. (fludarabine phosphate) has been tested in multiple phase I trials for solid tumors and acute leukemia, with myelosuppression identified as the main dose-limiting toxicity, particularly at higher doses for leukemia patients.

Despite severe neurotoxicity observed in acute leukemia patients at high doses, Fludara I.V. induces beneficial lymphopenia, which is effective in treating chronic lymphocytic leukemia and other lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trials with fludarabine phosphate. Von Hoff, DD.[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]

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 61 patients undergoing hematopoietic stem cell transplantation with a reduced-intensity conditioning regimen that included total marrow lymphoid irradiation (TMLI), fludarabine, and melphalan, the treatment was found to be feasible and safe, with a median follow-up of 7.4 years.

Long-term outcomes showed a 5-year overall survival rate of 42% and an event-free survival rate of 41%, indicating that while the treatment is well tolerated, further dosage adjustments of TMLI may be necessary to enhance disease control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total Marrow Lymphoid Irradiation/Fludarabine/ Melphalan Conditioning for Allogeneic Hematopoietic Cell Transplantation. Jensen, LG., Stiller, T., Wong, JYC., et al.[2019]

The combination of melphalan and 153Sm-EDTMP can effectively ablate bone marrow in WAG rats, but using both together at high doses can lead to high mortality (80%).

By administering 153Sm-EDTMP and melphalan sequentially, the mortality rate was significantly reduced to 7%, demonstrating a safer and effective approach for bone marrow ablation while allowing for recovery through marrow transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

153Sm-EDTMP and melphalan chemoradiotherapy regimen for bone marrow ablation prior to marrow transplantation: an experimental model in the rat. Turner, JH., Claringbold, PG., Berger, JD., et al.[2019]

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]

Citations

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