Low-Dose Cyclophosphamide for Blood Cancers

Recruiting in Palo Alto (17 mi)

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-hematologic cancer, others

No Placebo Group

Breakthrough Therapy

Approved in 4 Jurisdictions

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.

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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.

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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.

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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

Patients must have a histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation limited to one of the following: Acute myeloid leukemia (AML) of intermediate or adverse risk disease by the 2017 European LeukemiaNet criteria in first morphologic complete remission (<5% blasts in the bone marrow, no detectable abnormal peripheral blasts, and no extramedullary disease) AML of any risk in second or subsequent morphologic complete remission B-cell acute lymphoblastic leukemia in first or subsequent complete remission T-cell acute lymphoblastic leukemia with minimal residual disease detected after first line therapy and/or adverse genetics (no NOTCH1/FBXW7 mutation or presence of N/K-RAS mutation and/or PTEN gene alteration) Myelodysplastic syndrome of intermediate or higher score by the Revised International Prognostic Scoring System (IPSS-R) Primary myelofibrosis of intermediate-2 or higher risk by the DIPSS Chronic myelomonocytic leukemia Chronic myelogenous leukemia resistant to or intolerant of greater than or equal to 3 tyrosine kinase inhibitors or with history of accelerated phase or blast crisis B-cell lymphoma including Hodgkin lymphoma that has relapsed within 1 year of completion of primary treatment Chronic lymphocytic leukemia with 17p deletion and/or unmutated IgHV or refractory to or intolerant of both BTK and PI3K inhibitors Mature T or NK neoplasms as defined in the WHO guidelines of sufficient type and severity for allogeneic HCT based on the Prognostic Index for T-cell lymphoma (PIT) score of low-intermediate risk or higher or on recently published clinical practice guidelines Hematologic malignancy of dendritic cell or histiocytic cell type Multiple myeloma, stage III, relapsing after therapy with both a proteasome inhibitor and an immunomodulatory drug (IMiD) Age 15-65. Patients <18 years old must be at least 50 kg. Note: Because patients 15-17 years old and <50 kg are not able to be cared for on the adult oncology wards and by the investigative team, they are excluded. At least one potentially suitable HLA-haploidentical donor. Karnofsky performance score greater than or equal to 60 Adequate organ function defined as possessing all of the following: Cardiac ejection fraction greater than or equal to 45% by 2D ECHO; Forced expiratory volume-1 (FEV-1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) all of greater than or equal to 50% predicted; Estimated serum creatinine clearance of greater than or equal to 60 ml/minute/1.73m(2) calculated using eGRF in the clinical lab for adults and the Schwartz formula for pediatric subjects; Total bilirubin less than or equal to 2X the upper limit of normal; Alanine aminotransferase and aspartate aminotransferase less than or equal to 3X the upper limit of normal.

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

Myeloablative conditioning is toxic to the developing human fetus and is teratogenic. For this reason, the following measures apply: Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least one year post-transplant. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. WOCBP must have a negative serum or urine pregnancy test within 7 days prior to enrollment. Ability of subject or Legally Authorized Representative to understand and the willingness to sign a written informed consent document. Pediatric patients (<18 years of age) will provide assent, and the parent(s) or legal guardian(s) will provide informed consent. Subjects requiring standard therapies to prepare for HCT should be referred in remission if possible. However, these diseases are often aggressive and require swift evaluation for HCT while concurrently attempting to establish disease control through the administration of standard therapies. If ongoing therapy for the underlying disease outside of the NIH is not in the best interest of the subject according to the clinical judgment of the PI, then the subject may receive up to 2 cycles of standard treatment for his/her underlying hematologic malignancy as a bridge to HCT on this protocol, prior to starting the research phase of the study. The subject must have a Karnofsky performance status of greater than or equal to 60% at the start of the first cycle to proceed. If it becomes apparent that the subject will not be able to proceed to HCT, then he/she must come off study. Subjects receiving standard therapy will be told about the therapy, associated risks, potential benefits, alternatives to the proposed therapy, and the availability of receiving the same treatment elsewhere, outside of a research protocol.

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.

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Trial 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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

National Institutes of Health Clinical Center Bethesda, MD

Who Is Running the Clinical Trial?

National Cancer Institute (NCI) Lead Sponsor

National Institute of Neurological Disorders and Stroke (NINDS) Collaborator

References

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

Effects of endoxan on oxidative processes in model systems in vitro. [2014] Endoxan (cyclophosphamide) is a cyclic propylene phosphamide ester of nitrogen mustard. Endoxan--main advantage of chemotherapy is complete penetration of the tissues, reaching the most widely spread malignant cells. It is one of the most useful cytotoxics available today. Endoxan is a "transport form" and as such it has a selective tumour affinity. Endoxan is used for active treatment of all neoplastic diseases of the reticulo-endothelial system, e.g. lymphomas, lymphosarcomas, reticular-sarcomas, Hodgkin's disease, chronic lymphatic leukaemias, multiple myelomas. In our experiments Endoxan is equivalent with mean therapeutic the concentration used in chemotherapy in tumours, we suppose that at these levels Endoxan interact with renal cells and probably induce or inhibits new generation of superoxide free forms in the same tissue. Endoxan was tested at renal supernatant and free enzyme model systems, for superoxide-scavenging and antioxidante activity. The ability of Endoxan to interact with the superoxide radical, to influence their generation and probably to change the levels of lipid peroxidation in model systems were investigated. The ability of Endoxane to affect Fe2+-induced lipid peroxidation in a renal supernatant was studied. The results show that Endoxan in a concentration range of 10(-4); 10(-5) M has small but significant effect. The values for the control samples without Endoxan, are compared. We found a dose-dependent superoxide-scavenging effect of the drug in xanthite/xanthine oxidase system for generation of superoxide. According to obtained results lndoxan could be used in insertion in a liposomes and this could impact lndoxan tissue penetration.

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] Thirty-six patients were entered on this study to determine the pharmacology, bioavailability, and toxicity of three different oral formulations of cyclophosphamide (Cytoxan, Endoxan, and an investigational direct compression tablet). Patients were randomized with respect to the order in which they received the different oral cyclophosphamide preparations, and received each one for two weeks followed by a two week washout period. Concurrent chemotherapy was allowed provided it remained constant across all 3 courses of cyclophosphamide. Plasma concentrations of cyclophosphamide and phosphoramide mustard were measured by gas chromatography with electron capture detection. Peak plasma cyclophosphamide concentrations and times to peak plasma cyclophosphamide and phosphoramide mustard preparations were significantly greater for Endoxan than for Cytoxan and the investigational direct compression tablet. Drug area under the concentration-time curve (AUC), bioavailability, and plasma elimination half-life could not be reliably calculated for Endoxan but were similar for Cytoxan and the investigational formulation. Based on AUC comparisons, bioavailability of parent compound (relative to an oral cyclophosphamide solution) was 85% for Cytoxan and 69% for the investigational formulation. This difference was not significant. There were no significant differences between the 3 formulations with respect to any individual type of toxicity, although the investigational formulation tended to be associated with somewhat less overall toxicity (p = 0.08).

3. England pubmed.ncbi.nlm.nih.gov

Cyclophosphamide and cancer: golden anniversary. [2023] Cyclophosphamide remains one of the most successful and widely utilized antineoplastic drugs. Moreover, it is also a potent immunosuppressive agent and the most commonly used drug in blood and marrow transplantation (BMT). It was initially synthesized to selectively target cancer cells, although the hypothesized mechanism of tumor specificity (activation by cancer cell phosphamidases) transpired to be irrelevant to its activity. Nevertheless, cyclophosphamide's unique metabolism and inactivation by aldehyde dehydrogenase is responsible for its distinct cytotoxic properties. Differential cellular expression of aldehyde dehydrogenase has an effect on the anticancer therapeutic index and immunosuppressive properties of cyclophosphamide. This Review highlights the chemistry, pharmacology, clinical toxic effects and current clinical applications of cyclophosphamide in cancer and autoimmune disorders. We also discuss the development of high-dose cyclophosphamide for BMT and the treatment of autoimmune diseases.

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

Cyclophosphamide (Cytoxan). A review on relevant pharmacology and clinical uses. [2022] Cyclophosphamide (Cytoxan; Cy) is an alkylating agent with cytotoxic and immunosuppressive activities. The parent compound is inactive in vitro and exerts its biologic activity through metabolites, mainly phosphoramide mustard generated by hepatic microsomal enzymes. The exact mode of cytotoxic and immunosuppressive action of Cy at cellular level is not completely understood. Myelosuppression, hemorrhagic cystitis, alopecia, and gonadal damage are the main toxic effects. Available data suggest that Cy has carcinogenic potential in humans. Cy is widely used for cancer chemotherapy. As an immunosuppressive agent, it is successfully used in certain nonmalignant diseases in which autoimmune phenomena are established or suspected in the pathogenesis of the disease. It is the drug of choice in Wegener's granulomatosis. Extensive efforts are being made to synthesize Cy analogues with greater selective cytotoxic and immunosuppressive activity. Ifosfamide, a Cy analogue, appears to possess similar cytotoxic activity with less myelosuppression. Further research will help in synthesizing a Cy analogue with specific pharmacologic activity and reduced or absent harmful effects.

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

Bladder carcinoma following cyclophosphamide therapy. A case report. [2019] Cyclophosphamide was introduced in 1958 in an effort to minimize the side effects of nitrogen mustard. Cyclophosphamide (Cytoxan, Endoxan) is not an alkylating agent which has been used for the treatment of a variety of non-malignant as well as malignant diseases. It has also recently been the focus of considerable interest as an immunosuppressive agent, perhaps the most potent immunosuppressive drug that has been synthesized. Reports of urologic complications from this drug are haemorrhagic cystitis, vesical fibrosis and urothelial carcinoma.

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] Doxorubicin cardiotoxicity is one of the most serious side effects of the cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, regimen, especially among elderly patients. In the CEOP regimen, epirubicin was substituted for doxorubicin to reduce cardiotoxicity.

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

Cyclophosphamide-induced hemorrhagic cystitis in Ewing's sarcoma. [2017] Recent improvements in survival of patients with Ewing's sarcoma have been made since the addition of cyclophosphamide-based adjuvant chemotherapy to primary surgery and radiation. A potential limitation to cyclophosphamide use is its urotoxicity, primarily in the form of hemorrhagic cystitis. The incidence of this adverse effect in patients treated for Ewing's sarcoma has not been established. In a Mayo Clinic series of 116 patients with Ewing's sarcoma treated with cyclophosphamide, 17 (15%) developed hemorrhagic cystitis diagnosed on the basis of gross hematuria or cystoscopic findings (or both). Microscopic hematuria also occurred in 53% of patients (56 of 105 examined). The dose and duration of therapy appeared to be unrelated to the development of urotoxicity. Most patients recovered uneventfully with or without discontinuation of cyclophosphamide therapy, but a significant loss of blood occurred in three patients, and one patient required a cystectomy because of bladder fibrosis. Long-term follow-up is mandatory in these patients because of late recurrences of hemorrhagic cystitis or the possibility of bladder carcinoma. New therapies, directed at protecting the bladder from urotoxicity during cyclophosphamide treatment, are available.

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

Docetaxel and cyclophosphamide in patients with advanced solid tumors. [2018] This trial was designed to determine the recommended maximum tolerated dose (MTD), toxicity, pharmacokinetics, and efficacy of docetaxel (Taxotere) and cyclophosphamide (Cytoxan, Neosar) for phase II studies. Both drugs were administered to 39 patients with advanced solid tumors, 26 of whom had breast cancer. Docetaxel doses ranged from 60 to 85 mg/m2 and cyclophosphamide doses ranged from 600 to 800 mg/m2. All patients received steroid prophylaxis. The MTDs for patients with a history of prior chemotherapy were 75 mg/m2 of docetaxel and 700 mg/m2 of cyclophosphamide. For patients with no prior chemotherapy, the MTDs were 75 mg/m2 of docetaxel and 800 mg/m2 of cyclophosphamide. The dose-limiting toxicity was neutropenic fever, observed in 41% of patients and 13% of cycles. Addition of granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) did not permit further dose escalation, although it did result in briefer periods of neutropenia.