Reduced Intensity BMT for Solid Cancer

Recruiting at 6 trial locations

Overseen By Jasmine Brooks, BA

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Disqualifiers: HIV-positive, Pregnancy, Uncontrolled infections, 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 aims to determine if a less intense chemotherapy combined with a specific bone marrow transplant procedure is safe and feasible for individuals with very high-risk solid cancers. It involves administering drugs such as cyclophosphamide (Cytoxan or Neosar) and melphalan to help the body accept the new bone marrow. The trial seeks participants with difficult-to-treat cancers like neuroblastoma or stage 4 rhabdomyosarcoma after standard treatments have failed. Potential participants must have a related bone marrow donor with some genetic matches. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

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

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

A previous study using lower-intensity treatments with fludarabine and melphalan showed some possible side effects. However, these drugs are generally considered safe for treating blood cancers. When melphalan is used in smaller doses with fludarabine, it has proven safe and effective for transplants.

Research has shown that using low-dose total body irradiation (TBI) at 200 cGy, as in this study, does not significantly increase the risk of developing new cancers compared to chemotherapy alone. Cyclophosphamide, another drug in the treatment plan, carries known risks, such as potential bladder problems and cancer, but these risks can be managed with preventive measures.

Tacrolimus, which helps prevent organ rejection after transplants, carries a higher risk of certain cancers, like skin and lymph gland cancers. Despite these risks, it is widely used because it helps ensure transplant success.

Overall, while each treatment carries risks, they are generally well-tolerated when managed properly. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment approach because it uses a reduced intensity conditioning regimen that could potentially make bone marrow transplants more tolerable for patients with solid cancers. Unlike standard high-dose chemotherapy regimens, which can be very taxing on the body, this method uses lower doses of drugs like Melphalan and Cyclophosphamide, along with a specific type of radiation. This might lead to fewer side effects and a quicker recovery. Additionally, by incorporating post-transplant Cyclophosphamide and immunosuppressive agents like Tacrolimus and Mycophenolic acid, this approach aims to reduce the risk of graft-versus-host disease, a common complication in bone marrow transplants.

What evidence suggests that this trial's treatments could be effective for high-risk solid tumors?

Research has shown that a combination of fludarabine, melphalan, and low-dose total body irradiation holds promise for treating high-risk conditions. In this trial, participants will receive this combination as part of the reduced intensity conditioning regimen to prepare for a bone marrow transplant while minimizing side effects. Studies have found that this method aids in the recovery of blood cells and facilitates successful integration of donor cells. Additionally, low-dose total body irradiation is linked to a reduced chance of cancer recurrence within a year. These findings suggest that this treatment combination could be effective for patients with very high-risk solid tumors. ^{6 7 8 9 10}

Who Is on the Research Team?

Heather Symons, MD, MHS

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for patients with high-risk solid tumors who have a low chance of survival and haven't responded well to standard treatments. They need normal kidney function, decent heart function, and good overall health status. Participants must have a related donor who's partially genetically matched for bone marrow donation.

Inclusion Criteria

I have been diagnosed with neuroblastoma or ganglioneuroblastoma.

- Patients with high risk disease as defined in Appendix 1 whose autologous peripheral blood stem cell product is contaminated with neuroblastoma or who do not have an autologous product available

I have recovered from the side effects of my previous cancer treatments.

Exclusion Criteria

Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT).

My family and I prefer a specific donor for my treatment.

- Medically and psychologically fit and willing to donate

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment Evaluation

Documentation of detailed history, physical examination, and standard evaluation of cardiac, pulmonary, liver, and renal function

1 week

Preparative Regimen

Administration of Fludarabine, Melphalan, and Total Body Irradiation before bone marrow transplantation

7 days

Bone Marrow Transplantation

Bone marrow harvested and infused, followed by post-transplantation cyclophosphamide and immunosuppression regimen

90 days

Follow-up

Participants are monitored for safety, effectiveness, and incidence of GVHD and other complications

up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine
• Low Dose Total Body Irradiation
• Melphalan
• Tacrolimus

Trial Overview The study tests whether reduced intensity chemotherapy combined with haploidentical bone marrow transplant, post-transplant cyclophosphamide, and shortened tacrolimus treatment is safe and effective in patients with very high-risk solid tumors.

How Is the Trial Designed?

Group I: Reduced intensity conditioning Experimental Treatment 5 Interventions

Fludarabine IV infusion over 30 minutes on D-7 to D-3. The dose will be 30 mg/m2/dose (adjusted for renal function). Melphalan: IV infusion over 30-60 minutes, depending on volume, on D-2. The dose will be 100mg/m2.Total body irradiation: 200 cGy AP/PA with 4MV or 6MV photons at 8 12 cGy/min at the point of prescription (average separation of measurements at mediastinum, abdomen, and hips) will be administered in a single fraction on day -1. Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Tacrolimus begins on Day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 3 hours every 12 hours. Mycophenolic acid mofetil (MMF) F will be given at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Autologous stem cell transplant (ASCT) significantly improved outcomes for multiple myeloma (MM) patients, with an overall response rate of 80% and 64% survival rate over a 50-month follow-up period.

Patients who underwent ASCT in the early phase of MM showed better results, with a higher likelihood of achieving complete remission (CR) or very good partial remission (VGPR), which were predictive factors for longer overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Autologous stem cell transplantation in the treatment of multiple myeloma--single center experience]. Marjanović, S., Stamatović, D., Tukić, L., et al.[2019]

High-dose melphalan is the preferred chemotherapy for autologous stem cell transplantation in multiple myeloma patients, supported by earlier randomized trials.

Alternative treatment regimens involving different combinations of drugs and radiation have not shown better results than high-dose melphalan alone, according to multiple published studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple myeloma preparative regimens for high-dose therapy and autologous transplantation: what's new? Aljitawi, OS., McGuirk, JP.[2013]

Melphalan has been a key drug in hematopoietic stem cell transplantation (SCT) for over 50 years due to its strong myeloablative properties and effectiveness against various cancers, particularly multiple myeloma and lymphomas.

Combining melphalan with newer agents like bortezomib or lenalidomide may enhance its antitumor effects, while its low toxicity profile makes it a promising backbone for future cellular therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fifty years of melphalan use in hematopoietic stem cell transplantation. Bayraktar, UD., Bashir, Q., Qazilbash, M., et al.[2021]

In a meta-analysis of 10 studies involving 2855 patients with multiple myeloma, BUMEL-based conditioning was associated with longer progression-free survival (PFS) compared to high-dose melphalan (HDMEL), although overall survival (OS) was similar between the two regimens.

Patients receiving BUMEL experienced less gastrointestinal toxicity, while those on HDMEL had lower rates of mucositis and infections, suggesting that BUMEL may be a safer alternative for improving outcomes in autologous hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcomes of busulfan plus melphalan-based versus melphalan 200&#160;mg/m2 conditioning regimens for autologous hematopoietic&#160;stem cell transplantation in patients with multiple myeloma: a systematic review and meta-analysis. Gao, F., Lin, MS., You, JS., et al.[2021]

A study involving 63 multiple myeloma patients showed that the pharmacokinetics (PK) of generic melphalan (MEL) is comparable to that of the innovator formulation, indicating that both formulations behave similarly in the body.

Clinical outcomes, such as the severity of mucositis and the time to neutrophil and platelet engraftment, were not significantly different between patients receiving generic and innovator MEL, suggesting that the generic version is equally effective for autologous stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Efficacy of Generic Melphalan Is Comparable to Innovator Formulation in Patients With Multiple Myeloma Undergoing Autologous Stem Cell Transplantation. Pai, AA., Devasia, AJ., Panetta, JC., et al.[2022]

EVOMELA, a new formulation of melphalan that is free from propylene glycol, has been shown to be safe and effective for high-dose conditioning in autologous stem cell transplantation for multiple myeloma, with a 100% overall response rate in a study of 61 patients.

The study reported low incidences of severe side effects, such as grade 3 mucositis (10%) and stomatitis (5%), indicating that EVOMELA has an acceptable safety profile compared to traditional formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation. Hari, P., Aljitawi, OS., Arce-Lara, C., et al.[2017]

High-dose melphalan (HDMel) is commonly used for conditioning in autologous stem cell transplantation for multiple myeloma, and most studies classify its risk for causing chemotherapy-induced nausea and vomiting (CINV) as moderate to high.

An aprepitant-based three-drug regimen (including aprepitant, a serotonin receptor antagonist, and dexamethasone) is more effective for preventing CINV compared to a two-drug regimen, without increasing adverse events, making it the recommended choice for patients undergoing this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan and stem cell transplantation: review of the evidence and suggestions. Tendas, A., Marchesi, F., Mengarelli, A., et al.[2020]

In a study of 514 multiple myeloma patients, the propylene glycol-free formulation of melphalan (PGF-mel) showed similar efficacy to the conventional propylene glycol-based formulation (PG-mel) in terms of relapse rates after high-dose melphalan with autologous hematopoietic cell transplantation.

However, PGF-mel was associated with fewer severe adverse events like mucositis and febrile neutropenia, leading to a preference for PG-mel despite the potential benefits of PGF-mel, due to cost considerations and other factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Patient Outcomes With Two Different Formulations of Melphalan as Conditioning Chemotherapy for Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. Khan, AM., Yucebay, F., Zhao, Q., et al.[2023]

In a study of 101 lymphoma patients undergoing autologous stem cell transplantation, the mitoxantrone-melphalan (Mx-Mel) regimen showed similar efficacy to the BEAM regimen while being less toxic, making it a promising alternative for patients who cannot tolerate high cytotoxic treatments.

Although the BEAM regimen resulted in a statistically shorter time to neutrophil engraftment (10 days) compared to Mx-Mel (12 days), both regimens did not lead to significant differences in transplant-related complications, indicating that Mx-Mel is a safe option with effective outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Mitoxantrone-Melphalan and BEAM Conditioning Regimens in Patients with Lymphoma. Gunes, AK., Serin, I., Demir, I., et al.[2023]

In a phase II study involving 24 patients with multiple myeloma, a single dose of 200 mg/m2 of Evomela (PG-Free Melphalan) was found to be safe and resulted in a high overall response rate of 96%, with 75% achieving a very good partial response.

The study revealed significant variability in pharmacokinetics (PK) among patients, indicating that some individuals had much higher drug exposure, suggesting that future research could focus on optimizing dosing strategies to enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of High-Dose Propylene Glycol-Free Melphalan in Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation. Dhakal, B., D'Souza, A., Lakshman, A., et al.[2019]

Citations

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

Outcomes of Fludarabine, Melphalan and Total Body ... Fludarabine 30 mg/m 2 /d × 5 and melphalan 140 mg/m 2 × 1 (Flu-Mel140) is a commonly used reduced-intensity conditioning regimen.

2. ashpublications.org ashpublications.org/blood/article/101/4/1620/105963/Low-dose-total-body-irradiation-TBI-and

Low-dose total body irradiation (TBI) and fludarabine followed ... Patients were treated with fludarabine 30 mg/m2/d from days −4 to −2, 2 Gy total body irradiation on day 0, cyclosporine at 6.25 mg/kg twice daily from day −3, ...

3. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/87/NCT04191187/Prot_SAP_000.pdf

Reduced-Intensity Fludarabine, Melphalan, and Total Body ... Incidence of neutrophil recovery by day +56. • Incidence of platelet recovery by day +56. • Donor cell engraftment (chimerism) at day +30, +60, +90, ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S000649712057434X

Low-dose total body irradiation (TBI) and fludarabine ... Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/27764032/

The Addition of Low-Dose Total Body Irradiation to ... The TBI group had lower incidence of relapse at 1 year (15% vs 54%, P = 0.05). Conclusions: Overall, combination fludarabine-melphalan with low-dose TBI ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/212501s000lbl.pdf

cyclophosphamide injection - accessdata.fda.gov The risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis. ... Animal data suggest an increased risk of failed pregnancy and ...

7. pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov/compound/Cyclophosphamide

Cyclophosphamide | C7H15Cl2N2O2P | CID 2907 - PubChem Cyclophosphamide has been indicated as a human carcinogen (Group 1) by the International Agency for Research on Cancer (IARC). Exposure should be controlled by ...

8. go.drugbank.com go.drugbank.com/drugs/DB00531

Cyclophosphamide: Uses, Interactions, Mechanism of Action Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Modality: Small Molecule; Groups: Approved, Investigational; Structure. 3D.

9. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2023/210852s000lbl.pdf

Cyclophosphamide Injection - accessdata.fda.gov The risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis. ... Animal data suggest an increased risk of failed pregnancy and ...

10. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK553087/

Cyclophosphamide - StatPearls - NCBI Bookshelf - NIH Cyclophosphamide is a medication primarily used in the management and treatment of neoplasms, including multiple myeloma, sarcoma, and breast cancer.