Reduced-Dose Cyclophosphamide for Blood Cancer

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Christopher G Kanakry, M.D.

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

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

No Placebo Group

Breakthrough Therapy

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing if a lower dose of cyclophosphamide after a bone marrow transplant can help adults with difficult-to-treat blood cancers. The aim is to prevent complications from donor cells attacking the body while reducing side effects. The study focuses on patients who are older, less fit, or have not had success with other treatments.

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.

What data supports the effectiveness of the drug cyclophosphamide for blood cancer?

Cyclophosphamide, also known as Endoxan, is effective in treating various blood cancers like lymphomas and leukemias due to its ability to penetrate tissues and target widely spread cancer cells. It has been shown to have a significant effect in reducing oxidative stress, which may contribute to its effectiveness in cancer treatment. ^{1 2 3 4 5}

Is reduced-dose cyclophosphamide generally safe for humans?

Cyclophosphamide, also known as Cytoxan or Endoxan, has been linked to some safety concerns, including bladder issues like hemorrhagic cystitis (bleeding in the bladder) and an increased risk of bladder cancer, especially with long-term use. However, many patients recover from these side effects, and new treatments are available to protect the bladder during therapy. ^{1 2 3 6 7}

How is the drug cyclophosphamide unique in treating blood cancer?

Cyclophosphamide is unique because it is a 'transport form' with selective tumor affinity, allowing it to penetrate tissues and target widely spread cancer cells effectively. It is also known for its dual role as a cytotoxic (cell-killing) and immunosuppressive agent, making it versatile in treating both malignant and certain non-malignant diseases. ^{1 2 3 8 9}

Research Team

Christopher G Kanakry, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

Trial Timeline

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

Treatment Details

Interventions

• Cyclophosphamide (Alkylating agents)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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]

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]

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]

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 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]

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]

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]

References

1. Serbia pubmed.ncbi.nlm.nih.gov

Effects of endoxan on oxidative processes in model systems in vitro. [2014]

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

Pharmacology, relative bioavailability, and toxicity of three different oral cyclophosphamide preparations in a randomized, cross-over study. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Bladder carcinoma following cyclophosphamide therapy. A case report. [2019]

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

Timed-sequential high-dose cyclophosphamide and vincristine in the treatment of multiple myeloma. [2019]

5. United States 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. [2017]

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

Cyclophosphamide-induced hemorrhagic cystitis in Ewing's sarcoma. [2017]

7. France pubmed.ncbi.nlm.nih.gov

[Bladder neoplasms and cyclophosphamide. Apropos pf 3 cases amd review of the literature]. [2017]

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

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

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

Cyclophosphamide (Cytoxan). A review on relevant pharmacology and clinical uses. [2022]