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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a lower dose of cyclophosphamide (also known as Cytoxan, Neosar, or Endoxan) can improve transplant success with fewer side effects for people with certain blood cancers. Stem cell or bone marrow transplants can cure or control these cancers, but complications sometimes arise when donor cells attack the recipient's body. The trial explores whether reducing the dose and duration of certain drugs can still protect patients effectively. It seeks participants with leukemia, lymphoma, or multiple myeloma that cannot be cured with standard treatments and are at high risk of recurrence without a transplant, along with their healthy adult relatives. As a Phase 1, Phase 2 trial, it aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

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.

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

Studies have shown that cyclophosphamide, a drug often used in cancer treatments, is generally well-tolerated. It treats various cancers, including those affecting the blood, lymph system, and nerves. However, it can cause side effects like nausea, hair loss, and a low white blood cell count, which might increase infection risk.

Research indicates that mycophenolate mofetil prevents organ rejection in transplant patients. It is known to increase the risk of certain cancers, such as lymphoma and skin cancer. Discussing these risks with a healthcare provider is important.

The current study is in its early stages, so researchers are closely monitoring for side effects. This phase involves careful evaluation of treatment tolerance. If these drugs have been approved for other conditions, it generally indicates a good safety profile, but the specific context and dosing in this study might differ. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the use of low-dose cyclophosphamide (PTCy) in treating blood cancers because it offers a potentially safer alternative to higher doses used in standard treatments, which can lead to severe side effects. Unlike traditional therapies that often involve high doses, this approach uses de-escalating doses to minimize toxicity while still aiming to provide effective protection against complications like acute graft versus host disease (GVHD), a common issue in bone marrow transplants. Additionally, the de-escalation of Mycophenolate Mofetil (MMF) duration is being explored to further reduce side effects, potentially improving patient outcomes and quality of life.

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

Research has shown that cyclophosphamide (Cy) can help prevent complications after stem cell or bone marrow transplants for blood cancers. One study demonstrated a 69% success rate with a low dose of Cy, meaning nearly 7 out of 10 patients responded well. This trial includes a treatment arm where participants receive low-dose Cy to assess its effectiveness. Mycophenolate mofetil (MMF) is another drug used in this trial, with separate arms evaluating its duration and efficacy. MMF reduces the risk of serious complications by calming harmful immune responses. Using a lower dose of Cy with a shorter MMF treatment might offer the same benefits while potentially reducing side effects. ^{6 7 8 9 10}

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?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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, 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12263227/

Low-Dose Cyclophosphamide Enhances the Tumoricidal ... This study aimed to investigate the potential role of low-dose cyclophosphamide (Cy) as a radiosensitizer by evaluating its impact on the immune response ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10240086/

Continuous low-dose cyclophosphamide plus prednisone in ... The objective response rate (ORR) was 69% (29/42), and the median OS was 22.2 and 3.5 months for the responders and non-responders, respectively ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265025028046

CT-696: Results of Low-Dose Cyclophosphamide in GVHD ... Diagnoses were acute myeloid leukemia (62.5%), B-cell acute lymphoblastic leukemia (31.3%), and T-cell acute lymphoblastic leukemia (6.2%), all in hematologic ...

4. 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.

5. aacrjournals.org aacrjournals.org/clincancerres/article/12/10/3092/284654/Phase-II-Clinical-Trial-Results-Involving

Phase II Clinical Trial Results Involving Treatment with Low ... Browder et al. (1) have shown that giving low doses of cyclophosphamide every 6 days to mice bearing transplanted tumors markedly inhibited growth, even in a ...

6. 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.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2019/203856s003lbl.pdf

cyclophosphamide capsules - accessdata.fda.gov Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development ...

8. mayoclinic.org mayoclinic.org/drugs-supplements/cyclophosphamide-oral-route-intravenous-route/description/drg-20063307

Cyclophosphamide (oral route, intravenous route) Cyclophosphamide is used to treat cancer of the ovaries, breast, blood and lymph system, and nerves (mainly in children).

9. hillman.upmc.com hillman.upmc.com/patients/community-support/education/chemotherapy-drugs/cyclophosphamide-high-dose-for-sct

Cyclophosphamide Cytoxan®, Neosar®) Cyclophosphamide is given in the vein to treat cancer and suppress the immune system. Find side effects, allergic reactions, and food and drug interactions.

10. go.drugbank.com go.drugbank.com/drugs/DB00531

Cyclophosphamide: Uses, Interactions, Mechanism of Action Cyclophosphamide for intravenous injection is indicated for the treatment of a number of malignancies, including: Hodgkin's disease, lymphocytic lymphoma, mixed ...