Reduced-Dose Cyclophosphamide for Blood Cancer

Recruiting at 1 trial location

Overseen By Christopher G Kanakry, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: Uncontrolled illness, Active non-hematopoietic cancer, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

320 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a lower dose of the chemotherapy drug cyclophosphamide (also known as Cytoxan, Neosar, or Endoxan) to improve blood or bone marrow transplants for certain blood cancers. The goal is to determine if a smaller dose can effectively prevent complications like graft-versus-host disease (GVHD), where donor cells might attack the recipient's body, while reducing side effects. Suitable candidates include those whose blood cancer hasn't responded well to standard treatments or are at high risk of recurrence without a transplant. Participants must commit to a hospital stay, regular follow-up visits, and provide various samples for research. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on any investigational drugs, you must have completed them at least 2 weeks before starting the trial.

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

Research has shown that using a lower dose of cyclophosphamide after a bone marrow transplant can help treat challenging blood cancers. In studies, patients who received this reduced dose demonstrated encouraging survival rates. Two years after treatment, about 77% of patients remained alive, and around 58% had not experienced a recurrence of their cancer.

Importantly, the treatment showed a low rate of serious side effects, with few infections and only one early heart-related issue reported. Cyclophosphamide, already approved for other uses, suggests general safety.

This ongoing research aims to confirm if a lower dose can provide the same benefits with fewer side effects. Researchers closely monitor participants to ensure their safety. This approach could mean fewer problems for patients while still effectively treating their cancer. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the trial involving reduced-dose cyclophosphamide for blood cancer because it explores a potentially safer way to use an established medication. Unlike the standard high-dose cyclophosphamide treatments, which can be tough on patients due to severe side effects, this approach aims to maintain effectiveness while minimizing toxicity. The trial specifically looks at how well the reduced-dose works for older patients or those unfit for more aggressive treatment, potentially broadening the treatment options for those who currently have limited choices. By finding a balance between effectiveness and tolerability, this trial could lead to better quality of life for patients undergoing treatment.

What evidence suggests that reduced-dose cyclophosphamide might be an effective treatment for blood cancer?

Research has shown that cyclophosphamide can reduce graft-versus-host disease (GVHD) after a bone marrow transplant. Even at a lower dose, it provides sufficient immune suppression to support the transplant and prevent GVHD. Some participants in this trial will receive reduced-dose cyclophosphamide. Studies have found that this approach lowers the risk of non-cancer-related death to as low as 16% after two years, with overall survival rates reaching up to 70%. These findings suggest that a lower dose can be effective while potentially reducing side effects. The goal is to balance safety and success in treating challenging blood cancer cases. ^{1 2 4 6 7}

Who Is on the Research Team?

Christopher G Kanakry, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults aged 18-85 with blood cancers not responding well to standard treatments or at high relapse risk, and their donors. Participants must have a suitable donor, agree to contraception use, and meet specific health criteria like adequate organ function. Excluded are those on other investigational drugs, with poorly controlled cancer or significant unrelated illnesses.

Inclusion Criteria

My organs are functioning well.

Ability to understand and sign a written informed consent document

I have a related donor over 12 years old willing to donate and participate in research.

Exclusion Criteria

My cancer is not well-managed and I need a transplant.

I do not have any severe illnesses that would make a transplant unsafe for me.

Breastfeeding mothers

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for medical history, physical exam, and tests

Pre-transplant Conditioning

Participants receive nonmyeloablative conditioning with fludarabine, cyclophosphamide, and total body irradiation

1 week

Inpatient stay

Transplantation and Immediate Post-transplant Care

Participants receive the bone marrow transplant and post-transplant cyclophosphamide on days +3 and +4

4-6 weeks

Inpatient stay

Follow-up

Participants are monitored for safety and effectiveness after treatment, including weekly visits for 3 months post-discharge and periodic visits up to 5 years

5 years

Weekly visits for 3 months, then every 3-12 months

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide

Trial Overview The trial is testing if a lower dose of cyclophosphamide can reduce side effects while still preventing graft-versus-host disease in bone marrow transplant patients. It includes chemotherapy, radiation, and post-transplant medications over several weeks with follow-up visits up to five years.

How Is the Trial Designed?

Group I: Younger, HLA-mismatched Experimental Treatment 8 Interventions

Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor

Group II: Younger, HLA-matched Experimental Treatment 8 Interventions

Subjects age 18-60 unfit for MAC with hematologic malignancies and an HLA-matched related or unrelated donor

Group III: Older, HLA-mismatched Experimental Treatment 8 Interventions

Subjects age 60-85 with hematologic malignancies and an HLA-haploidentical or HLA-mismatched unrelated donor

Group IV: Older, HLA-matched Experimental Treatment 8 Interventions

Subjects age 60-85 with hematologic malignancies and an HLA-matched related or unrelated donor

Group V: Donors Active Control 1 Intervention

Collection of research samples on bone marrow donors

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Cyclophosphamide treatment, especially at cumulative doses over 20 g and for durations longer than one year, significantly increases the risk of developing bladder cancer, with a relative risk estimated between 7 and 9.

Bladder cancers that arise after cyclophosphamide treatment are typically transitional cell carcinomas, and the occurrence is linked to the drug's metabolites, particularly acrolein, suggesting a need for careful monitoring and limiting its use in non-malignant conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Bladder neoplasms and cyclophosphamide. Apropos pf 3 cases amd review of the literature]. Alexandre, J., Lévy, V., Hunault, M., et al.[2017]

In a trial involving 39 patients with advanced solid tumors, the maximum tolerated doses (MTDs) for docetaxel and cyclophosphamide were determined to be 75 mg/m2 for both drugs, regardless of prior chemotherapy history, indicating a consistent safety threshold.

The most common dose-limiting toxicity was neutropenic fever, occurring in 41% of patients, highlighting the need for careful monitoring and management of blood cell counts during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel and cyclophosphamide in patients with advanced solid tumors. Valero, V.[2018]

In a study involving 2,305 women with primary breast cancer, intensifying the dose of cyclophosphamide in combination with doxorubicin did not lead to significant improvements in disease-free survival (DFS) or overall survival after 5 years.

Increasing the total dose of cyclophosphamide resulted in higher grade 4 toxicity, indicating that such intensification may not be safe or beneficial for patients outside of clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22. Fisher, B., Anderson, S., Wickerham, DL., et al.[2017]

In a study involving 36 patients, Endoxan showed significantly higher peak plasma concentrations of cyclophosphamide compared to Cytoxan and an investigational tablet, indicating it may be more effective in delivering the drug quickly.

While all formulations had similar bioavailability and toxicity profiles, the investigational formulation was associated with slightly lower overall toxicity, suggesting it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology, relative bioavailability, and toxicity of three different oral cyclophosphamide preparations in a randomized, cross-over study. Stewart, DJ., Morgan, LR., Verma, S., et al.[2019]

Endoxan (cyclophosphamide) is an effective chemotherapy drug that penetrates tissues well, making it useful for treating various cancers, particularly those of the reticulo-endothelial system, such as lymphomas and leukemias.

In laboratory tests, Endoxan demonstrated a dose-dependent ability to scavenge superoxide radicals and influence lipid peroxidation, suggesting it may have antioxidant properties that could enhance its therapeutic effects when used in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of endoxan on oxidative processes in model systems in vitro. Mileva, M., Traikov, L., Deliyska, B.[2014]

Cyclophosphamide, introduced in 1958, is a potent immunosuppressive agent used to treat various diseases, both malignant and non-malignant.

Despite its therapeutic benefits, cyclophosphamide is associated with significant urologic complications, including hemorrhagic cystitis, vesical fibrosis, and an increased risk of urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bladder carcinoma following cyclophosphamide therapy. A case report. Kiesswetter, H., Baloch, N., Flamm, J.[2019]

Cyclophosphamide (Cy) is an effective chemotherapy drug that works by converting into active metabolites, primarily phosphoramide mustard, which have cytotoxic and immunosuppressive effects, although its exact mechanism is not fully understood.

While Cy is effective for treating cancers and certain autoimmune diseases like Wegener's granulomatosis, it has significant side effects, including myelosuppression and potential carcinogenicity, prompting research into safer analogues like ifosfamide that may offer similar benefits with fewer harmful effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclophosphamide (Cytoxan). A review on relevant pharmacology and clinical uses. Ahmed, AR., Hombal, SM.[2022]

In a study of 116 patients with Ewing's sarcoma treated with cyclophosphamide, 15% developed hemorrhagic cystitis, indicating a significant risk of this adverse effect associated with the chemotherapy.

While most patients recovered without major issues, there were serious complications in some cases, including significant blood loss and one patient requiring a cystectomy, highlighting the need for long-term monitoring and potential protective therapies for bladder health during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclophosphamide-induced hemorrhagic cystitis in Ewing's sarcoma. Stillwell, TJ., Benson, RC., Burgert, EO.[2017]

A study involving 108 patients with refractory or relapsing multiple myeloma found that a single high dose of cyclophosphamide (2400 mg/m2) was more toxic and did not improve treatment response compared to standard dosing over four days.

Adding vincristine (1.4 mg/m2) at a specific time after cyclophosphamide did not enhance the treatment's effectiveness, showing no significant differences in response rates or survival between the treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Timed-sequential high-dose cyclophosphamide and vincristine in the treatment of multiple myeloma. Lenhard, RE., Kalish, LA., Oken, MM., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11274764/

Reduced Dose of Post-Transplant Cyclophosphamide with ... These results suggest that PTCY 40 mg/kg/day on a +3/+4 schedule provides adequate immunosuppression to allow for engraftment and prevent clinically significant ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36585459/

Reduced post-transplant cyclophosphamide doses in ... At 2 years, non-relapse mortality was 16% and 31%, progression-free survival 65% and 49%, overall survival 70% and 56%, and GVHD-free, relapse- ...

3. withpower.com withpower.com/trial/phase-2-hematologic-neoplasms-8-2021-12bc6

Reduced-Dose Cyclophosphamide for Blood Cancer This trial is testing if a lower dose of cyclophosphamide after a bone marrow transplant can help adults with difficult-to-treat blood cancers.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06001385?term=AREA%5BConditionSearch%5D(B-cell%20prolymphocytic%20leukemia%20OR%20%22B%20prolymphocytic%20leukaemia%22%20OR%20%22%20B%20prolymphocytic%20leukemia%22%20OR%20%22%20B-PLL%22)%20AND%20AREA%5BOverallStatus%5D(NOT_YET_RECRUITING%20OR%20RECRUITING)&rank=3

NCT06001385 | HLA-Mismatched Unrelated Donor ... The goal of this clinical trial is to determine the effectiveness of Reduced Dose Post-Transplant Cyclophosphamide (PTCy) in patients with hematologic ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2666636724006092

Efficacy of a Modified Post-Transplant Cyclophosphamide ... The present study demonstrates that the modified PTCy, with a reduced dose of 40 mg on days +3 and +4, may be an effective regimen for URD-HSCT in patients ...

6. mdpi.com mdpi.com/2072-6694/16/14/2567

Reduced Dose of Post-Transplant Cyclophosphamide with ... Two-year overall survival and relapse-free survival were 77.1% and 58.3%. There were low incidences of infections and only one early cardiac event. These ...

7. researchgate.net researchgate.net/publication/366702994_Reduced_post-transplant_cyclophosphamide_doses_in_haploidentical_hematopoietic_cell_transplantation_for_elderly_patients_with_hematological_malignancies

(PDF) Reduced post-transplant cyclophosphamide doses ... At 2 years, non-relapse mortality was 16% and 31%, progression-free survival 65% and 49%, overall survival 70% and 56%, and GVHD-free, relapse- ...