Low-Dose Cyclophosphamide for Blood Cancers

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-hematologic 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: 2

400 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Stem cell or bone marrow transplants can cure or control blood cancers. Sometimes the donor cells see the recipient's body as foreign. This can cause complications. A high dose of the drug cyclophosphamide (PTCy) can help reduce these risks. Researchers want to see if a lower dose of PTCy can have the same benefits. Based on encouraging results from the first part of the study, researchers now are investigating whether a lower dose of PTCy can allow other immunosuppression to be decreased. Objective: To see if a lower dose of PTCy and now also shorter duration of another immunosuppressant called mycophenolate mofetil will help people with blood cancers have a more successful transplant and fewer side effects. Eligibility: People ages 15-65 with leukemia, lymphoma, or multiple myeloma that is not curable with standard therapy and is at high risk of returning without transplant, and their healthy adult relatives Design: Transplant participants will be screened with: Blood, urine, breathing, and heart tests Scans Chest x-ray Bone marrow samples: A needle inserted into the participant s pelvis will remove marrow and a bone fragment. Transplant recipients will stay at the hospital and be prepped with chemotherapy over 6 days for the transplant. They will get stem cells through a catheter in the chest or neck. They will get the cyclophosphamide chemotherapy. They will stay in the hospital about 4 more weeks. They will have blood transfusions. They will have frequent blood tests and 2 bone marrow samples within 1 year after the transplant. Donor participants will be screened with: Blood, urine, and heart tests Chest x-ray Scans Donor participants will have bone marrow taken from their pelvis or stem cells taken from their blood. For the blood donation, blood will be taken from a vein in one arm, move through a machine to remove white blood cells, and be returned through a vein in the other arm. Participation will last up to 5 years....

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on any investigational drugs, you must have completed them at least 4 weeks before starting the trial.

What data supports the effectiveness of the drug Cyclophosphamide for blood cancers?

Cyclophosphamide is widely used as an antineoplastic (cancer-fighting) drug and is particularly effective in treating various blood cancers like lymphomas and leukemias. It works by penetrating tissues to reach and destroy cancer cells, and its effectiveness is supported by its long-standing use in cancer treatment and blood and marrow transplantation. ^{1 2 3 4 5}

Is low-dose cyclophosphamide generally safe for humans?

Cyclophosphamide, also known as Endoxan or Cytoxan, has been used for various conditions, but it can cause side effects like bladder issues, including hemorrhagic cystitis (bleeding in the bladder) and, in rare cases, bladder cancer. Most patients recover from these side effects, but long-term monitoring is recommended. ^{1 2 5 6 7}

How is the drug cyclophosphamide unique for treating blood cancers?

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 also has immunosuppressive properties, making it versatile for treating both malignant and certain non-malignant diseases. ^{1 2 4 5 8}

Research Team

Christopher G Kanakry, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for people aged 15-65 with certain high-risk blood cancers like leukemia, lymphoma, or multiple myeloma that standard treatments can't cure. They must be in good health otherwise and have a relative who can donate stem cells. Pregnant women and those with severe illnesses or recent other cancer treatments are excluded.

Inclusion Criteria

I have a related donor over 12 years old willing to donate for my treatment and research.

Exclusion Criteria

You cannot participate in this study if you are currently taking any other experimental medications or have taken them in the past 4 weeks. You also cannot participate if you have uncontrolled illnesses such as active infections, heart failure, or mental health issues that would interfere with the study requirements. If you have had previous bone marrow transplant or have a sibling donor who is eligible for bone marrow donation, you cannot participate. Pregnant or breastfeeding women are also excluded from the study. Additionally, if you have had non-hematopoietic cancer that has spread or is not responding to treatment, or if it is not possible to cure it, you cannot participate in the study.

N/A

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for blood, urine, breathing, heart tests, scans, chest x-ray, and bone marrow samples

Pre-transplant Chemotherapy

Participants receive chemotherapy over 6 days to prepare for the transplant

6 days

Inpatient stay

Transplant and Initial Treatment

Participants receive stem cells and cyclophosphamide chemotherapy, followed by a hospital stay for monitoring and blood transfusions

4 weeks

Inpatient stay

Follow-up

Participants are monitored for safety and effectiveness after treatment, including blood tests and bone marrow samples

1 year

Frequent visits for blood tests and 2 bone marrow samples

Long-term Follow-up

Participants are monitored for long-term outcomes and side effects

Up to 5 years

Treatment Details

Interventions

• Cyclophosphamide
• Mycophenolate Mofetil

Trial Overview Researchers are testing if lower doses of the drug cyclophosphamide (PTCy) combined with shorter use of another immunosuppressant can make bone marrow transplants more successful for blood cancer patients while reducing side effects.

Participant Groups

Group I: Phase II efficacy of reduced duration MMF Experimental Treatment 5 Interventions

MMF at duration identified from de-escalation evaluation.

Group II: Phase II Efficacy Experimental Treatment 5 Interventions

PTCy at shortest duration, safe dose (from Phase I) to assess efficacy at providing adequate protection from grade 3-4 acute GVHD (up to 14 additional patients)

Group III: Phase I duration de-escalation of MMF Experimental Treatment 5 Interventions

MMF at de-escalating duration (days +5 to +18 only, no MMF))

Group IV: Phase I Pilot for Comparative Data Experimental Treatment 5 Interventions

Standard PTCy 50 mg/kg/day on days +3 and +4, in a small pilot (up to 5 evaluable patients) for comparative data

Group V: Phase I Dose De-escalation Experimental Treatment 5 Interventions

PTCy at de-escalating doses (25 mg/kg/day on days +3 and +4, and PTCy 25 mg/kg on day +4) to assess for safety and determine Phase II dose (up to 12 evaluable patients)

Group VI: Donor Arm Active Control 1 Intervention

Collection of bone marrow and/or PBSC (Up to 40 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+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

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 is a highly effective antineoplastic and immunosuppressive drug, widely used in cancer treatment and blood and marrow transplantation, with its unique metabolism playing a key role in its cytotoxic effects.

The drug's efficacy and safety profile are influenced by the expression of aldehyde dehydrogenase in cells, which affects its anticancer activity and immunosuppressive properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclophosphamide and cancer: golden anniversary. Emadi, A., Jones, RJ., Brodsky, RA.[2023]

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]

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]

The CEOP chemotherapy regimen, which substitutes epirubicin for doxorubicin, demonstrated a high efficacy with a complete remission rate of 64.3% in 186 patients with intermediate- or high-grade non-Hodgkin lymphoma, particularly benefiting elderly patients.

Long-term follow-up showed that 79.8% of patients who achieved complete remission remained disease-free at a median of 86.9 months, indicating that CEOP is not only effective but also well-tolerated, with no deaths from cardiac toxicity reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of patients with intermediate or high-grade non-Hodgkin lymphoma treated with a combination of cyclophosphamide, epirubicin, vincristine, and prednisone. Rossini, F., Terruzzi, E., Perego, D., et al.[2015]

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]

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]

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. England pubmed.ncbi.nlm.nih.gov

Cyclophosphamide and cancer: golden anniversary. [2023]

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

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

5. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Long-term follow-up of patients with intermediate or high-grade non-Hodgkin lymphoma treated with a combination of cyclophosphamide, epirubicin, vincristine, and prednisone. [2015]

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

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

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

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