High-Dose Methotrexate for Breast Cancer

Recruiting at 2 trial locations

Overseen By Cindy Miller

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Wake Forest University Health Sciences

Must not be taking: Salicylates, NSAIDs, Sulfonamides

Disqualifiers: Heart failure, Diabetes insipidus, Mucositis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 6

Duration: 12 weeks

16 Participants Needed

Trial Summary

What is the purpose of this trial?

Management of leptomeningeal disease (LMD) in patients with metastatic breast cancer is an area of unmet clinical need. High-dose methotrexate (HD-MTX) is known to have activity against breast cancer and in contrast to other systemic chemotherapeutics, it penetrates the blood brain barrier, targets areas of poor cerebrospinal fluid flow, may penetrate bulky leptomeningeal disease, and provide treatment to systemic disease burden. While two retrospective studies have suggested activity of HD-MTX in LMD in patients with breast cancer, no prospective data are available to inform its inclusion in treatment regimens. Thus, while HD-MTX is included in the NCCN Guidelines for LMD and while it is used to varying degrees in cancer centers across the nation, this is more representative of the lack of available therapies for LMD as opposed to strong evidence-based data. This phase II, prospective study will evaluate systemic, intravenous HD-MTX in breast cancer patients with leptomeningeal metastasis with or without brain parenchymal metastasis.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but you cannot use salicylates, non-steroidal anti-inflammatory drugs, or sulfonamide medications within one week of starting methotrexate. Existing anti-HER2 therapy can be continued as recommended in the guidelines.

What data supports the effectiveness of the drug High-Dose Methotrexate for breast cancer?

High-dose methotrexate has shown effectiveness in other cancers, such as non-Hodgkin's lymphoma, where some patients experienced remission, and in malignant melanoma, where some patients had disease stabilization. This suggests potential benefits in treating breast cancer, although direct evidence for breast cancer is not provided. ^{1 2 3 4 5}

Is high-dose methotrexate generally safe for humans?

High-dose methotrexate can be safely given to most people, but it may cause serious side effects in some. Studies have shown that adjusting the dose can help maintain safe levels and reduce the risk of these side effects. ^{2 3 4 6 7}

How does high-dose methotrexate differ from other breast cancer drugs?

High-dose methotrexate is unique because it involves administering large amounts of the drug with leucovorin rescue to reduce toxicity, allowing it to reach therapeutic levels in the central nervous system, which is not typical for standard methotrexate treatments. This approach can be effective for advanced breast cancer, but it requires careful monitoring due to potential side effects like central nervous system dysfunction and renal issues. ^{8 9 10 11 12}

Research Team

Roy E. Strowd

Principal Investigator

Wake Forest University Health Sciences

Eligibility Criteria

This trial is for adults over 18 with invasive breast cancer that's triple negative, HER2-positive, or hormone refractory. They must have leptomeningeal metastasis confirmed by tests and be in good physical condition (ECOG 0-1). People can't join if they've had certain treatments recently, are pregnant/breastfeeding, have severe heart failure or fluid collections like ascites, adverse reactions to methotrexate before, uncontrolled diseases, or are on conflicting medications.

Inclusion Criteria

My organs are functioning well.

I am fully active or can carry out light work.

My breast cancer is triple negative, HER2-positive, or hormone refractory.

Exclusion Criteria

You had a bad reaction to methotrexate before.

I have had partial brain radiotherapy in the last two weeks.

I haven't taken methotrexate in the last year.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive high-dose methotrexate (HD-MTX) every 2 weeks until disease progression or death

12 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Participants are monitored for overall survival and progression-free survival

Up to 2 years

Treatment Details

Interventions

• High-dose Methotrexate

Trial Overview The study is testing high-dose Methotrexate (HD-MTX) given intravenously to see if it helps patients with breast cancer who also have leptomeningeal metastasis. It's a phase II trial aiming to provide prospective data since current use of HD-MTX lacks strong evidence but is suggested by retrospective studies and included in NCCN Guidelines due to limited treatment options.

Participant Groups

Group I: High-dose Methotrexate (8 gm/m2; HD-MTX) Experimental Treatment 1 Intervention

Enrolled patients will undergo treatment with HD-MTX (8 g/m2) as per current standard practice on an every 2 week schedule until disease progression or death from any cause. Treatment will be performed according to standard clinical practice. Surveillance imaging with or without cytologic evaluation will be performed as per standard clinical practice after every 2 cycles (\~28 days). Treatment will continue until there is unequivocal evidence of clinical or radiographic CNS or systemic disease progression, death from any cause, or intolerance.

High-dose Methotrexate is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Methotrexate for:

• Breast cancer
• Osteosarcoma
• Non-Hodgkin's lymphoma
• Leukaemia
• Psoriasis
• Rheumatoid arthritis

Approved in United States as Methotrexate for:

• Breast cancer
• Osteosarcoma
• Non-Hodgkin's lymphoma
• Leukaemia
• Psoriasis
• Rheumatoid arthritis

Approved in Canada as Methotrexate for:

• Breast cancer
• Osteosarcoma
• Non-Hodgkin's lymphoma
• Leukaemia
• Psoriasis
• Rheumatoid arthritis

Approved in Japan as Methotrexate for:

• Breast cancer
• Osteosarcoma
• Non-Hodgkin's lymphoma
• Leukaemia
• Psoriasis
• Rheumatoid arthritis

Who Is Running the Clinical Trial?

Wake Forest University Health Sciences

Lead Sponsor

Trials

1,432

Recruited

2,506,000+

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborator

Trials

578

Recruited

33,600+

Findings from Research

In a phase II trial involving 17 patients with advanced hepatocellular carcinoma, edatrexate showed minimal therapeutic efficacy, with no complete or partial responses and only two minor responses lasting less than 12 weeks.

While some patients experienced a decrease in serum alpha-fetoprotein levels, indicating a potential biological effect, the treatment was associated with significant grade 3 and 4 toxicities, including granulocytopenia and anemia, raising concerns about its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of edatrexate in patients with advanced hepatocellular carcinoma. Pazdur, R., Moore, DF., Bready, B., et al.[2020]

In a study of 294 patients undergoing high-dose methotrexate (HD-MTX) chemotherapy, a modified dose-adjustment program (Program 2) was found to be more effective in maintaining target MTX concentration levels compared to a fixed dose reduction program (Program 1).

While Program 2 allowed for higher MTX doses and better concentration maintenance, it was associated with a higher incidence of abnormal serum potassium levels and prolonged myelosuppression in certain patients, but overall toxicity levels were not significantly different between the two programs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-individualization Efficiently Maintains Sufficient Exposure to Methotrexate without Additional Toxicity in High-dose Methotrexate Regimens for Pediatric Acute Lymphoblastic Leukemia. Shen, YQ., Wang, ZJ., Wu, XY., et al.[2022]

Individualizing high-dose methotrexate (HDMTX) based on previous clearance in 485 patients with acute lymphoblastic leukemia led to 70% and 63% of doses being within 20% of target plasma concentrations, significantly better than the 60% achieved with conventional dosing (p < 0.001).

The individualized approach resulted in a much lower incidence of excessively high plasma concentrations (1.3% vs. 7.3% with conventional therapy, p < 0.001) and maintained a low rate of severe toxicities (8.5% of courses), indicating improved safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments. Pauley, JL., Panetta, JC., Crews, KR., et al.[2022]

In a study involving 28 patients with advanced malignant melanoma who did not respond to previous chemotherapy, high-dose methotrexate treatment resulted in one patient showing an objective response and seven patients experiencing disease stabilization for an average of 4 months.

While there were five cases of serious toxicity, none were fatal, indicating that high-dose methotrexate can have significant side effects but may still offer some therapeutic benefit in this difficult-to-treat patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose methotrexate in malignant melanoma. Karakousis, CP., Carlson, M.[2013]

In a study involving five patients with non-Hodgkin's lymphoma who did not respond to standard chemotherapy, high doses of methotrexate (MTX) and leucovorin (LCV) resulted in complete remission in 2 patients and partial remission in 2 others.

The treatment was well-tolerated, with no severe side effects reported, suggesting that high-dose MTX and LCV could be a viable option for patients with resistant malignant lymphoma, although the remission duration was short, indicating the need for additional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[High dose of methotrexate-leucovorin treatment in advanced non-Hodgkin's lymphoma]. Kawarabayashi, K., Yoshikawa, T., Sannomiya, Y., et al.[2013]

A comprehensive evidence-based practice guideline for high-dose methotrexate (HDMTX) therapy was developed through a rigorous process involving multidisciplinary experts and input from 124 patients, ensuring that patient values and preferences were considered.

The guideline includes 28 recommendations covering critical aspects of HDMTX administration, such as pre-treatment evaluations, dosing regimens, therapeutic drug monitoring, and management of toxicities, with 12 of these recommendations being classified as strong, enhancing the safety and efficacy of HDMTX therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Medication therapy of high-dose methotrexate: An evidence-based practice guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. Song, Z., Hu, Y., Liu, S., et al.[2022]

Outpatient administration of high dose methotrexate (HDMTX) at 12 g/m² is safe and feasible, with 82% of 708 courses successfully completed in a pediatric day hospital setting.

Supportive therapy with leucovorin is crucial, as nearly half of the patients required dose adjustments based on methotrexate levels, with mild nephrotoxicity and reversible liver enzyme elevation being the most common side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Memorial Sloan Kettering Cancer Center experience with outpatient administration of high dose methotrexate with leucovorin rescue. Zelcer, S., Kellick, M., Wexler, LH., et al.[2013]

High-dose methotrexate with leucovorin rescue (HDMTX-LCV) can be safely administered weekly, with myelosuppression occurring in 28% of patients, primarily due to mild reversible nephrotoxicity.

While HDMTX-LCV shows promising tumor regression rates in various cancers (up to 59% in non-Hodgkin's lymphoma), it is not recommended for standard metastatic cancer treatment due to potential toxicity and similar efficacy to conventional methotrexate doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High dose methotrexate with leucovorin rescue. Rationale and spectrum of antitumor activity. Frei, E., Blum, RH., Pitman, SW., et al.[2019]

In a phase II trial involving 32 patients with heavily pretreated metastatic breast cancer, the high-dose chemotherapy regimen of mitoxantrone, etoposide, and thiotepa (MVT) showed significant activity, achieving a 61% overall response rate and a 23% complete response rate.

Despite a high incidence of grade 3 or 4 mucositis (69%), the second cycle of MVT did not increase morbidity or mortality compared to the first cycle, suggesting that this regimen can be safely administered to patients who have limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of mitoxantrone, etoposide, and thiotepa with autologous marrow support for patients with relapsed breast cancer. Wallerstein, R., Spitzer, G., Dunphy, F., et al.[2017]

The maximum tolerated doses for the chemotherapy combination of Thiotepa, Mitoxantrone, and Methotrexate in 12 patients with metastatic breast cancer were established, with significant myelosuppression as the main toxicity observed.

Out of the 12 patients, 5 showed a partial response to the treatment, with durations ranging from 1.25 to 10 months, indicating potential effectiveness, especially in patients who had previously received doxorubicin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot trial of TMM (thiotepa, mitoxantrone and methotrexate) chemotherapy for metastatic breast cancer. Bhardwaj, S., Holland, JF.[2020]

In a study of 27 patients with advanced recurrent breast cancer, high-dose methotrexate combined with citrovorum factor rescue resulted in a 29% objective tumor regression rate, with a median response duration of 26 weeks.

While the treatment was generally well-tolerated, significant side effects included mild myelosuppression and central nervous system dysfunction in 22% of patients, leading to treatment discontinuation in some cases due to renal dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose methotrexate for advanced breast cancer. Yap, HY., Blumenschein, GR., Yap, BS., et al.[2013]

In a study of 184 patients with acute lymphoblastic leukemia and T-non-Hodgkin lymphoma, monitoring methotrexate levels at 54 hours after high-dose administration was found to be a safe approach, with only 0.5% of cycles resulting in significant toxicity.

Out of 598 cycles of high-dose methotrexate, 88.7% were managed with just a single drug level check, and despite 43.5% experiencing delayed methotrexate clearance, there were no deaths, suggesting that this simplified monitoring strategy can be effective in resource-limited settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safe administration of high-dose methotrexate with minimal drug level monitoring: Experience from a center in north India. Dhingra, H., Kalra, M., Mahajan, A.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Phase II trial of edatrexate in patients with advanced hepatocellular carcinoma. [2020]

2. China pubmed.ncbi.nlm.nih.gov

Dose-individualization Efficiently Maintains Sufficient Exposure to Methotrexate without Additional Toxicity in High-dose Methotrexate Regimens for Pediatric Acute Lymphoblastic Leukemia. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments. [2022]

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

High-dose methotrexate in malignant melanoma. [2013]

5. Japan pubmed.ncbi.nlm.nih.gov

[High dose of methotrexate-leucovorin treatment in advanced non-Hodgkin's lymphoma]. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Medication therapy of high-dose methotrexate: An evidence-based practice guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. [2022]

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

The Memorial Sloan Kettering Cancer Center experience with outpatient administration of high dose methotrexate with leucovorin rescue. [2013]

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

High dose methotrexate with leucovorin rescue. Rationale and spectrum of antitumor activity. [2019]

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

A phase II study of mitoxantrone, etoposide, and thiotepa with autologous marrow support for patients with relapsed breast cancer. [2017]

10. England pubmed.ncbi.nlm.nih.gov

A pilot trial of TMM (thiotepa, mitoxantrone and methotrexate) chemotherapy for metastatic breast cancer. [2020]

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

High-dose methotrexate for advanced breast cancer. [2013]

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

Safe administration of high-dose methotrexate with minimal drug level monitoring: Experience from a center in north India. [2021]