Chemotherapy + Stem Cell Transplant for Blood Cancers

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Inotuzumab, Gemtuzumab

Disqualifiers: HIV, Uncontrolled infections, Hepatitis B/C, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to treat blood cancers using a combination of chemotherapy and stem cell transplants. It aims to determine how effectively drugs like busulfan and fludarabine phosphate can stop cancer cells from growing and spreading. After the transplant, cyclophosphamide is used to prevent the immune system from attacking the new cells. People with high-risk blood cancers who have a related or matched donor might be suitable candidates for this trial. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in cancer care.

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 shows that the combination of busulfan and fludarabine phosphate, used in this trial, is generally safe for treating blood cancers. Studies have found that administering busulfan intravenously, rather than orally, improves absorption, making it easier to control and safer. This method is already common in many treatment plans.

For fludarabine phosphate, research highlights the importance of the correct dosage for safety. Incorrect dosing can impact survival rates. However, when used correctly, it is a standard part of treatments for blood cancers, such as chronic lymphocytic leukemia.

Both drugs have been used in cancer treatments for a long time, providing a good understanding of their mechanisms and side effects. While all treatments carry risks, existing evidence suggests these drugs are generally well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it combines chemotherapy with stem cell transplants to tackle blood cancers such as leukemia and lymphoma. Unlike standard treatments that often use chemotherapy alone, this approach aims to reset the patient’s immune system by replacing damaged cells with healthy stem cells from donors. The trial is unique because it explores both matched and haploidentical (partially matched) donor transplants, which could expand the pool of possible donors. Additionally, the use of medications like busulfan, fludarabine phosphate, and thiotepa, alongside post-transplant immunosuppressants like tacrolimus and mycophenolate mofetil, is designed to improve the success rate and reduce complications. Researchers hope these combined strategies will offer more effective and personalized treatment options for patients with blood cancers.

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

Research has shown that busulfan and fludarabine phosphate effectively treat blood cancers when used in stem cell transplants. In this trial, participants will receive different combinations of these drugs within various treatment groups. Studies indicate that busulfan attaches to the DNA of cancer cells, hindering their survival. It is commonly used in stem cell transplants and is considered a standard part of treatment. Fludarabine phosphate is also important; it has been linked to better survival rates when used before a stem cell transplant. Together, these drugs help stop cancer cell growth and prepare the body to receive new, healthy stem cells. This combination aims to improve the chances of successful treatment for blood cancers. ^{1 5 6 7 8}

Who Is on the Research Team?

Uday R. Popat

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with high-risk blood cancers like various leukemias, lymphomas, and myeloma. They should have a poor prognosis without transplant therapy and can be in remission or relapsed. Participants need functioning major organs, no active hepatitis B/C or HIV, not pregnant nor breastfeeding, willing to use contraception if applicable, and must have a suitable donor for stem cell transplant.

Inclusion Criteria

My heart pumps blood well.

My lung function tests are within normal limits, or if I'm a child under 7, my oxygen level is 92% or higher on room air.

My kidneys are functioning well enough to filter waste.

Exclusion Criteria

I have previously been treated with inotuzumab or gemtuzumab.

I am HIV positive.

I have had heart disease related to my arteries.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy and Transplantation

Patients receive busulfan, fludarabine phosphate, and cyclophosphamide, followed by stem cell transplantation

Approximately 3 weeks

Multiple visits for chemotherapy administration and transplantation

Post-Transplantation Treatment

Patients receive cyclophosphamide and immunosuppressive therapy with tacrolimus and mycophenolate mofetil

Up to 3 months

Regular visits for monitoring and medication administration

Follow-up

Participants are monitored for safety, effectiveness, and incidence of graft versus host disease

Up to 3 years

Periodic visits for long-term monitoring

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Cyclophosphamide
• Fludarabine Phosphate

Trial Overview The study tests busulfan and fludarabine phosphate chemotherapy followed by donor stem cell transplant with post-transplant cyclophosphamide treatment. It aims to see how well these drugs work together to stop cancer growth by killing cells or preventing their spread while reducing the risk of graft-versus-host disease.

How Is the Trial Designed?

Group I: Group VI (matched or haploidentical transplant, chemotherapy) Experimental Treatment 10 Interventions

Patients receiving fully matched or haploidentical donor transplant receive busulfan IV over 3 hours on days -20, -13, and -6 to -3, a lower dose of thiotepa IV over 4 hours on day -7, fludarabine phosphate IV over 1 hour on days -6 to -3. Patients undergo stem cell transplantation IV on day 0. Patients then receive cyclophosphamide IV over 3 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously or PO BID for up to 3 months and mycophenolate mofetil PO TID.

Group II: Group V (haploidentical donor transplant, chemotherapy) Experimental Treatment 10 Interventions

Patients receive busulfan IV over 3 hours on days -20, -13, and -6 to -3, a lower dose of thiotepa IV over 4 hours on day -7, fludarabine phosphate IV over 1 hour on days -6 to -3. Patients undergo stem cell transplantation IV on day 0. Patients then receive cyclophosphamide IV over 3 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously or PO BID for up to 3 months and mycophenolate mofetil PO TID.

Group III: Group IV (matched donor transplant, chemotherapy) Experimental Treatment 8 Interventions

Patients receiving haploidentical related donor transplant, diagnosis of myelofibrosis, \> 60 years old, or patients with comorbidity scores \> 3 will go in Group 3 or 4. If patients with comorbidity score \>3, then the principal investigator is the final arbiter of eligibility for comorbidity score \> 3. Busulfan is administered at the dose calculated to achieve a total (including first two doses delivered on day -20 and day -13) system exposure of 20,000 +/- 12% uMol-min based on the pharmacokinetic studies.

Group IV: Group III (haploidentical donor transplant, chemotherapy) Experimental Treatment 10 Interventions

Patients receiving haploidentical related donor transplant, diagnosis of myelofibrosis, \> 60 years old, or patients with comorbidity scores \> 3 will go in Group 3 or 4. If patients with comorbidity score \> 3, then the principal investigator is the final arbiter of eligibility for comorbidity score \> 3. Busulfan is administered at the dose calculated to achieve a total (including first two doses delivered on day -20 and day -13) system exposure of 20,000 +/- 12% uMol-min based on the pharmacokinetic studies.

Group V: Group II (matched donor transplant, chemotherapy) Experimental Treatment 8 Interventions

Patients receive busulfan IV over 3 hours on days -13, -12, and -6 to -3, fludarabine phosphate IV over 1 hour on days -6 to -3. Patients undergo stem cell transplantation IV on day 0. Patients then receive cyclophosphamide IV over 3 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously or PO BID for up to 3 months.

Group VI: Group I (haploidentical donor transplant, chemotherapy) Experimental Treatment 10 Interventions

Patients receive busulfan IV over 3 hours on days -13, -12, and -6 to -3, thiotepa IV over 4 hours on day -7, fludarabine phosphate IV over 1 hour on days -6 to -3. Patients undergo stem cell transplantation IV on day 0. Patients then receive cyclophosphamide IV over 3 hours on days 3 and 4. Beginning on day 5, patients receive tacrolimus IV continuously or PO BID for up to 3 months and mycophenolate mofetil PO TID.

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

Approved in United States as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Malignant lymphoma
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 62 patients undergoing reduced-intensity conditioning for stem cell transplantation, therapeutic dose monitoring of oral busulfan did not significantly impact post-transplant outcomes compared to standard dosing.

The presence of chronic graft-versus-host disease was identified as a strong predictor of overall survival and leukemia-free survival, highlighting its importance in patient outcomes after transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning allogeneic blood stem cell transplantation with fludarabine and oral busulfan with or without pharmacokinetically targeted busulfan dosing in patients with myeloid leukemia ineligible for conventional conditioning. Martino, R., Pérez-Simón, JA., Moreno, E., et al.[2013]

In a study of 32 patients with acute myeloid leukemia in first complete remission, the busulfan/fludarabine (Bu/Flu) conditioning regimen resulted in significantly lower transplant-related toxicity compared to the busulfan/cyclophosphamide (Bu/Cy) regimen, with a lower incidence of severe side effects (68.8% vs. 25.0%).

Both regimens showed similar efficacy in terms of overall survival and event-free survival rates, indicating that Bu/Flu is a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A comparison of toxicity and efficacy between busulfan plus fludarabine and busulfan plus cyclophosphamide for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia]. Liu, H., Fan, ZP., Jiang, QL., et al.[2014]

In a study comparing two treatment regimens for children undergoing hematopoietic cell transplantation, the combination of fludarabine and busulfan (FluBu) showed similar survival rates to busulfan and cyclophosphamide (BuCy), with 2-year survival rates of 82% for FluBu and 78% for BuCy.

The FluBu regimen was associated with significantly lower toxicity, including reduced rates of lung injury, veno-occlusive disease, and infections, as well as a shorter duration of neutropenia, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity. Bartelink, IH., van Reij, EM., Gerhardt, CE., et al.[2014]

The study evaluated a myeloablative conditioning regimen using fludarabine and busulfan in 70 patients with acute leukemia, showing similar efficacy to the traditional BuCy regimen with overall survival at 71% and disease-free survival at 64%.

Fludarabine and busulfan resulted in a high incidence of mucositis (93%) but lower transplant-related adverse effects compared to BuCy, suggesting it could be a safer alternative, although modifications may be needed for optimal anti-leukemic effects in specific leukemia types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and busulfan as a myeloablative conditioning regimen for allogeneic stem cell transplantation in high- and standard-risk leukemic patients. Iravani, M., Evazi, MR., Mousavi, SA., et al.[2013]

In a study involving 16 patients with hematological malignancies, the pharmacokinetics of fludarabine were assessed before and after administration of busulfan, showing no significant changes in key parameters such as clearance and half-life.

The results suggest that there is unlikely to be a clinically relevant drug interaction between busulfan and fludarabine, supporting their combined use in conditioning regimens for stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. Bonin, M., Pursche, S., Bergeman, T., et al.[2013]

In a study of 415 adult patients with relapsed and refractory non-Hodgkin lymphoma, those receiving the reduced-intensity conditioning regimen (Flu/Bu2) had a significantly better 5-year overall survival rate of 50.6% compared to 32.2% for those receiving the myeloablative regimen (Flu/Bu4).

The higher nonrelapse mortality (NRM) rate in the Flu/Bu4 group (31.9%) compared to the Flu/Bu2 group (15.7%) contributed to the poorer overall survival, indicating that the choice of conditioning regimen is critical for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine plus reduced-intensity busulfan versus fludarabine plus myeloablative busulfan in patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation. Kamijo, K., Shimomura, Y., Shinohara, A., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4261695/

Busulfan in Hematopoietic Stem Cell Transplantation - PMC Available clinical results indicate, that the IV BuFlu conditioning regimens are safe and effective, and are being adopted as “standard of care” preparative ...

2. astctjournal.org astctjournal.org/article/S1083-8791(08)01100-2/fulltext

Busulfan in Hematopoietic Stem Cell Transplantation This study showed that the Cy dose reduction did not compromise the antileukemic activity, but significantly reduced the toxicity of the conditioning regimen.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40373977/

Busulfan Once Versus Four Times Daily Bu administered once a day shows benefit both in the short and long term compared to Bu administered 4 times a day, but data are heterogeneus, Bu-Q24 being more ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT00990249

Study Details | NCT00990249 | Busulfan Plus Clofarabine ... Busulfan is designed to bind to DNA (the genetic material of cells), which may cause cancer cells to die. It is commonly used in stem cell transplants.

5. nature.com nature.com/articles/s41409-022-01641-6

Impact of busulfan pharmacokinetics on outcome in adult ... Busulfan (Bu) is widely used in conditioning regimens before allogeneic hematopoietic cell transplantation, with variable metabolism due to interindividual ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT00238433

Busulfan, Melphalan, and Thiotepa in Treating Patients ... RATIONALE: Chemotherapy, such as busulfan, melphalan, and thiotepa, may destroy cancerous blood-forming cells (stem cells) in the blood and bone marrow.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/99/20954_medr_P13.pdf

120-Day Safety Update Report Review - accessdata.fda.gov Thiotepa, busulfan, and cyclophosphamide: a new preparative regimen for autologous marrow or blood stem cell transplantation in high-risk multiple myeloma. Dix, ...

8. ashpublications.org ashpublications.org/bloodadvances/article/7/18/5225/496607/Association-between-busulfan-exposure-and-survival

Association between busulfan exposure and survival in ... Busulfan exposure is associated with OS; 5-year survival with an exposure of ≥59.5 vs <59.5 mg × h/L was 67% (95% CI, 59-76) vs 40%.