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 phase I trial studies the side effects and the best dose of intensity modulated total marrow irradiation (IMTMI) when given together with fludarabine phosphate and melphalan in treating patients with cancers of the blood (hematologic) that have returned after a period of improvement (relapsed) undergoing a second donor stem cell transplant. IMTMI is a type of radiation therapy to the bone marrow that may be less toxic and may also reduce the chances of cancer to return. Giving fludarabine phosphate, melphalan, and IMTMI before a donor stem cell transplant may help stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

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.

Is the combination of Intensity Modulated Total Marrow Irradiation, Fludarabine, and Melphalan safe for humans?

The combination of Intensity Modulated Total Marrow Irradiation (IM-TMI), Fludarabine, and Melphalan has been studied in humans, showing that it is generally feasible and safe, though it can cause side effects like mucositis (painful inflammation and ulceration of the mucous membranes lining the digestive tract) and, in rare cases, severe heart problems. The most common serious side effect was mucositis, and some patients experienced heart issues, so careful monitoring is important. ^{1 2 3 4 5}

How is the treatment of Intensity Modulated Total Marrow Irradiation with Fludarabine Phosphate and Melphalan different from other treatments for hematologic cancers?

This treatment is unique because it combines intensity-modulated total marrow irradiation (IM-TMI) with the drugs fludarabine and melphalan, specifically for patients undergoing a second or greater allogeneic stem cell transplant. This approach aims to improve disease control while managing toxicity, offering a tailored conditioning regimen that may be more effective for certain patients compared to standard reduced-intensity conditioning regimens. ^{3 4 5 6 7}

What data supports the effectiveness of the treatment Intensity Modulated Total Marrow Irradiation + Fludarabine Phosphate + Melphalan for hematologic cancers?

Research shows that combining fludarabine and melphalan with total body or marrow irradiation can improve survival and disease control in patients with hematologic cancers. Specifically, a study found that a regimen including these components improved progression-free survival and overall survival compared to other regimens, indicating its potential effectiveness. ^{3 4 5 6 8}

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

I have AML or high-risk MDS and am undergoing a second stem cell transplant for relapse, or I have another blood cancer as decided by my doctors.

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

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]

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 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]

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 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]

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]

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]

Citations

1. England 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. [2019]

2. 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]

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

Total Marrow Lymphoid Irradiation/Fludarabine/ Melphalan Conditioning for Allogeneic Hematopoietic Cell Transplantation. [2019]

4. 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]

5. 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]

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

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

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

Phase I clinical trials with fludarabine phosphate. [2013]

8. 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]