Deferoxamine for Meningeal Carcinomatosis

Recruiting at 13 trial locations

Overseen By Helena Yu, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Iron chelators, Ascorbic acid

Disqualifiers: CNS irradiation, Pregnancy, Psychiatric illness, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing whether injecting deferoxamine into the fluid around the brain and spinal cord is safe for people with cancer that has spread there. It focuses on patients with non-small cell lung cancer. The drug works by reducing the iron that cancer cells need to grow. Deferoxamine is an iron chelator approved by the FDA, commonly used to treat iron-overload diseases and has shown anticancer activity by depleting cancer cells of iron.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot use systemic iron chelators within 4 weeks of the first dose or ascorbic acid or prochlorperazine within 2 weeks of the first dose. If you are on a systemic treatment controlling your extracranial disease, you may continue it during the study.

What data supports the effectiveness of the drug Deferoxamine (DFO) for treating meningeal carcinomatosis?

Deferoxamine (DFO) has been shown to effectively reduce iron levels in patients with severe iron overload, as seen in a study where continuous infusion led to significant decreases in iron levels and high patient compliance. While this is not directly related to meningeal carcinomatosis, it suggests that DFO can be effective in managing conditions involving excess iron. ^{1 2 3 4 5}

Is deferoxamine safe for use in humans?

Deferoxamine (DFO) has been studied for safety in patients with acute intracerebral hemorrhage, and the research aimed to evaluate its safety and tolerability, suggesting it has been considered safe enough for human trials. ^{6 7 8 9 10}

How does the drug Deferoxamine (DFO) differ from other treatments for meningeal carcinomatosis?

Deferoxamine (DFO) is unique because it is an iron chelator, meaning it binds to iron and removes it from the body, which can inhibit the growth of certain cancer cells. Unlike traditional chemotherapy, DFO's mechanism involves reducing iron availability, which is essential for cancer cell proliferation, and it can be administered intranasally to target the brain more effectively. ^{6 7 8 11 12}

Research Team

Jessica Wilcox, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults over 18 with leptomeningeal metastasis from solid tumors or NSCLC, who have a life expectancy of at least 8 weeks and can use effective contraception. They must be stable enough not to need immediate brain metastases treatment, able to handle an Ommaya reservoir (a device placed in the brain for drug delivery), and have normal CSF flow.

Inclusion Criteria

I am 18 years old or older.

Life expectancy ≥ 8 weeks in the opinion of the Investigator

My cancer, including lung cancer, has spread to the lining of my brain or spinal cord.

Exclusion Criteria

I am on a treatment for my brain metastases that is currently working.

I have not had brain radiation within the last week.

I have not undergone whole-brain or craniospinal radiation therapy.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a Treatment

Participants receive intrathecal deferoxamine (IT-DFO) via Ommaya reservoir in an accelerated dose escalation fashion, with conversion to a traditional 3 + 3 dose escalation scheme. Dosing is twice per week during cycle 1, once per week during cycle 2, and once every 2 weeks for subsequent cycles until LM progression, intolerable toxicity, or death.

Varies by cohort, assessed for 28 days per cohort

Twice per week during cycle 1, once per week during cycle 2, once every 2 weeks for subsequent cycles

Phase 1b Treatment

Participants receive IT-DFO at the recommended phase 2 dose (RP2D) determined from phase 1a. Dosing is twice per week during cycle 1, once per week during cycle 2, and once every 2 weeks for subsequent cycles until LM progression, intolerable toxicity, or death. Early efficacy endpoints are assessed.

Until progression, intolerable toxicity, or death

Twice per week during cycle 1, once per week during cycle 2, once every 2 weeks for subsequent cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Deferoxamine (DFO) (Iron Chelator)

Trial Overview Researchers are testing Deferoxamine (DFO) given directly into the cerebrospinal fluid (CSF) to find a safe dose for treating leptomeningeal metastasis from solid tumor cancers. They aim to determine how DFO affects the body and its safety and effectiveness against non-small cell lung cancer-related metastasis.

Participant Groups

Group I: Deferoxamine (DFO) Experimental Treatment 1 Intervention

This study is an open-label, non-randomized, single-center, dose escalation phase 1a study of intrathecal deferoxamine (IT-DFO) in patients with leptomeningeal metastases (LM) from solid tumor malignancies, followed by a phase 1b dose expansion cohort at the recommended phase 2 dose (RP2D) in patients with LM from solid tumor malignancies. Study objectives will include safety (1a/1b), pharmacokinetics (PK) and pharmacodynamics (PD) of IT-DFO (1a), and preliminary anti-tumoral efficacy in patients with LM solid tumor malignancies (1b).

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Center for Experimental Therapeutics

Collaborator

Trials

1

Recruited

40+

F.M. KIRBY FOUNDATION

Collaborator

Trials

1

Recruited

40+

Findings from Research

Deferiprone (DFP) is identified as the most cost-effective iron chelation therapy for managing iron overload in patients with β-thalassemia major, based on a systematic review of eight cost-utility analyses involving nineteen studies.

Combination therapy of Deferoxamine (DFO) and DFP was found to be less cost-effective compared to using either DFO or DFP alone, indicating that monotherapy may be preferable in terms of cost-effectiveness for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Evaluation of Chelation Regimens for β-Thalassemia Major: a Systematic Review. Li, J., Lin, Y., Li, X., et al.[2022]

A new 24-hour continuous intravenous infusion of deferoxamine (CIV DFO) was tested in nine patients over approximately 15.7 months, showing excellent patient compliance at 93%.

This method significantly increased urinary iron excretion compared to traditional subcutaneous infusions and led to a 71% reduction in serum ferritin levels, indicating effective management of iron overload.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction in tissue iron stores with a new regimen of continuous ambulatory intravenous deferoxamine. Olivieri, NF., Berriman, AM., Tyler, BJ., et al.[2019]

In a phase II trial involving 20 patients with advanced squamous cell carcinoma of the head and neck, doxifluridine showed a response rate of 25%, with one complete remission and two partial remissions observed.

The treatment was associated with significant side effects, primarily myelosuppression, along with mild nausea, vomiting, stomatitis, and central nervous system effects, suggesting the need for careful monitoring and potential adjustments in dosing for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of doxifluridine in advanced squamous cell carcinoma of the head and neck. Abele, R., Kaplan, E., Grossenbacher, R., et al.[2019]

In a pilot study involving 16 patients with advanced colorectal cancer, the combination of folinic acid, 5-fluorouracil, and alpha-interferon resulted in a 25% objective response rate, with a median response duration and overall survival of 9.5 months.

Despite some effectiveness, the treatment caused significant toxicity, leading to dose reductions in 10 out of 16 patients, which prompted the closure of the study due to an unfavorable cost/benefit ratio.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High dose alpha-2b interferon + folinic acid in the modulation of 5-fluorouracil. A phase II study in advanced colorectal cancer with evidence of an unfavourable cost/benefit ratio. Labianca, R., Pancera, G., Tedeschi, L., et al.[2022]

In a study involving 42 patients with metastatic colorectal cancer, the combination of 5-fluorouracil (5-FU) and sodium folinate (S-FA) administered via a continuous 24-hour infusion was found to be a safe and effective second-line treatment, achieving a 9% objective response rate and halting tumor progression in 74% of patients.

The treatment resulted in a median survival of 14.7 months and a median time to tumor progression of 5.7 months, with manageable side effects including grade III/IV diarrhea in 19% of patients, indicating that the new formulation allows for convenient simultaneous administration of both drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line treatment of advanced colorectal cancer with a weekly simultaneous 24-hour infusion of 5-fluorouracil and sodium-folinate: a multicentre phase II trial. Kuhfahl, J., Steinbrecher, C., Wagner, T., et al.[2013]

In a study involving rats with acute myelogenous leukemia, treatment with deferoxamine (DFO), an iron chelator, did not significantly improve survival compared to untreated groups, indicating limited efficacy in vivo.

Even when using a high molecular weight polymeric conjugate of DFO designed for sustained drug levels, there was no major impact on survival, suggesting that achieving effective cytotoxic levels of DFO in this type of leukemia may not be feasible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Failure to alter the course of acute myelogenous leukemia in the rat with subcutaneous deferoxamine. Blatt, J., Boegel, F., Hedlund, BE., et al.[2019]

Intranasal administration of deferoxamine (DFO) significantly increases its concentration in the brain compared to intravenous delivery, achieving up to 200 times more targeted delivery to the cortex, which is crucial for treating stroke.

In animal studies, both pre-treatment and post-treatment with intranasal DFO reduced stroke damage by 55%, indicating its potential as an effective treatment and preventive measure for ischemic stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. Hanson, LR., Roeytenberg, A., Martinez, PM., et al.[2021]

Deferoxamine (DFO) effectively inhibits the proliferation of human myeloid leukemia cell lines (HL-60, HEL, U-937) in a dose-dependent manner, with significant effects observed at concentrations above 20 microM.

The antiproliferative effects of DFO are linked to a decrease in DNA synthesis, which can be reversed by adding iron salts, suggesting that DFO's mechanism of action involves iron chelation and its impact on cellular processes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antileukemic effects of deferoxamine on human myeloid leukemia cell lines. Becton, DL., Roberts, B.[2013]

Intranasal deferoxamine (IN DFO) significantly improved working memory in healthy mice compared to intraperitoneal (IP) DFO and saline controls, indicating that IN delivery is a more effective method for targeting the brain.

The memory enhancement observed with IN DFO treatment is linked to decreased GSK-3β activity and increased HIF-1α activity, suggesting a non-disease-specific mechanism that could be beneficial in various neurological conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal deferoxamine can improve memory in healthy C57 mice, suggesting a partially non-disease-specific pathway of functional neurologic improvement. Fine, JM., Kosyakovsky, J., Baillargeon, AM., et al.[2021]

A multicenter phase-I study involving 20 patients with spontaneous intracerebral hemorrhage (ICH) demonstrated that intravenous infusions of deferoxamine mesylate (DFO) are feasible and well-tolerated, with only 10% of subjects discontinuing due to adverse events.

The study identified a maximum tolerated dose of 62 mg/kg per day, and while some patients experienced mild blood-pressure-lowering effects, the overall safety profile was acceptable, paving the way for future efficacy studies of DFO in ICH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Selim, M., Yeatts, S., Goldstein, JN., et al.[2021]

Deferoxamine mesylate (DFO) significantly improved the tumor-to-blood ratio in 67Ga tumor imaging in tumor-bearing rats, particularly when administered 12 hours after the 67Ga injection.

In human studies, while DFO helped accelerate the excretion of 67Ga from the blood, it did not consistently enhance the quality of tumor images, indicating a complex relationship between DFO administration and imaging efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deferoxamine mesylate enhancement of 67Ga tumor-to-blood ratios and tumor imaging. Koizumi, K., Tonami, N., Hisada, K.[2019]

Deferoxamine (DFO) significantly enhances the neuronal differentiation of neural progenitor cells (NPCs) when used in acute doses (100 μM for 6 hours) in serum-free conditions, leading to increased expression of neuronal markers and decreased expression of glial markers.

The mechanism behind this effect involves the suppression of the Wnt/β-catenin pathway, which is triggered by DFO's ability to chelate intracellular iron, suggesting its potential as a neuroprotective agent in regenerative medicine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute course of deferoxamine promoted neuronal differentiation of neural progenitor cells through suppression of Wnt/β-catenin pathway: a novel efficient protocol for neuronal differentiation. Ziaei, A., Ardakani, MR., Hashemi, MS., et al.[2015]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Economic Evaluation of Chelation Regimens for β-Thalassemia Major: a Systematic Review. [2022]

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

Reduction in tissue iron stores with a new regimen of continuous ambulatory intravenous deferoxamine. [2019]

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

Phase II study of doxifluridine in advanced squamous cell carcinoma of the head and neck. [2019]

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

High dose alpha-2b interferon + folinic acid in the modulation of 5-fluorouracil. A phase II study in advanced colorectal cancer with evidence of an unfavourable cost/benefit ratio. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Second-line treatment of advanced colorectal cancer with a weekly simultaneous 24-hour infusion of 5-fluorouracil and sodium-folinate: a multicentre phase II trial. [2013]

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

Failure to alter the course of acute myelogenous leukemia in the rat with subcutaneous deferoxamine. [2019]

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

Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. [2021]

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

Antileukemic effects of deferoxamine on human myeloid leukemia cell lines. [2013]

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

Intranasal deferoxamine can improve memory in healthy C57 mice, suggesting a partially non-disease-specific pathway of functional neurologic improvement. [2021]

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

Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. [2021]

11. Germany pubmed.ncbi.nlm.nih.gov

Deferoxamine mesylate enhancement of 67Ga tumor-to-blood ratios and tumor imaging. [2019]

12. Ireland pubmed.ncbi.nlm.nih.gov

Acute course of deferoxamine promoted neuronal differentiation of neural progenitor cells through suppression of Wnt/β-catenin pathway: a novel efficient protocol for neuronal differentiation. [2015]