Deferoxamine for Meningeal Carcinomatosis
Recruiting in Palo Alto (17 mi)
+13 other locations
Overseen byJessica Wilcox, 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.
12345Is 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.
678910How 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.
6781112Eligibility 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.
+10 more
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.
+6 more
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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Deferoxamine (DFO)Experimental Treatment1 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).
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Memorial Sloan Kettering Cancer Center (All Protocol Activities)New York, NY
Memorial Sloan Kettering Suffolk - Commack (Limited Protocol Activities)Commack, NY
Memorial Sloan Kettering Nassau (Consent Only)Uniondale, NY
Memorial Sloan Kettering Bergen (Consent Only )Montvale, NJ
More Trial Locations
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Who Is Running the Clinical Trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
Center for Experimental TherapeuticsCollaborator
F.M. KIRBY FOUNDATIONCollaborator
References
Economic Evaluation of Chelation Regimens for β-Thalassemia Major: a Systematic Review. [2022]Deferoxamine (DFO) or Deferiprone (DFP) or Deferasirox (DFX) monotherapy and DFO and DFP combination therapy (DFO+DFP) were four commonly implemented now chelation regimens for the iron overloaded of β-thalassemia major. This systematic review aims to determine the cost-effectiveness of four chelation regimens and provide evidence for the rational use of chelation regimens for β-thalassemia major therapy in the clinic.
Reduction in tissue iron stores with a new regimen of continuous ambulatory intravenous deferoxamine. [2019]A new regimen of 24-hr ambulatory continuous intravenous infusion of deferoxamine (CIV DFO) through central venous ports was instituted in nine patients aged (mean +/- SD) 22.4 +/- 5.8 years over a period of 15.7 +/- 7.3 months. Central venous infusion sites were changed weekly in the clinic, eliminating the necessity for reconstitution of DFO and needle insertion at home. Because CIV DFO could be interrupted only by medical personnel, patient compliance was documented accurately; patients administered 93.0% +/- 3.2% of CIV DFO prescribed. Mean urinary iron excretion on CIV DFO (66.8 +/- 50.4 mg/24 hr) was significantly greater than that quantitated during 12-hr equivalent-dose subcutaneous DFO infusions (23.4 +/- 18.3 mg/24 hr; P less than 0.025). Mean serum ferritin declined by 71% over the treatment period (P less than 0.005). This regimen confers the advantages of uninterrupted exposure to DFO, is associated with excellent patient compliance, and should be considered in any patient with severe iron overload and erratic compliance with DFO.
Phase II study of doxifluridine in advanced squamous cell carcinoma of the head and neck. [2019]We conducted a phase II trial with 5'-deoxy-5-fluoridine (doxifluridine) in advanced squamous cell carcinoma of the head and neck. The drug was given at the dose of 4 g/m2 daily X 5 every 3 weeks. Twenty eligible patients entered this trial, 12 being evaluable for response to doxifluridine. The majority of these patients received previous treatment for cancer. One complete and two partial remissions were observed (25%). Drug-induced toxicity consisted mainly of myelosuppression, mild nausea and vomiting, stomatitis and central nervous system side-effects. Other dosages or schedules for doxifluridine administration might be explored in poor-risk patients.
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]The combination of folinic acid (FA) and 5-fluorouracil (5FU) is the most active systemic chemotherapy against advanced colorectal cancer. Experimental and clinical studies have suggested that the activity of 5FU can be improved by the addition of alpha-interferon (IFN). To evaluate the possibility of a double modulation of 5FU, a pilot study was conducted in the period July 1989-December 1989 with the following regimen: FA (200 mg/m2 i.v. bolus x 5 days) + 5FU (400 mg/m2 i.v. in 15 min x 5 days) + alpha-2b IFN (10 x 10(6) IU subcutaneously on alternate days). FA and 5FU administrations were repeated every 28 days; IFN was administered every week. In the 16 treated patients, 4 partial responses, 4 no changes, and 8 with progression of disease were observed, with an objective response rate of 25% (95% CI, 7.8%-55.1%). Median duration of response was 9.5 months, as was overall survival. Toxicity (fever, fatigue, neurotoxicity, stomatitis and diarrhea) was considerable and led to a reduction in IFN doses in 10/16 patients. Due to the unfavorable cost/benefit ratio, the study was closed and a new trial, with different doses and schedule of IFN, was started within the GISCAD (Italian Group for the Study of Digestive Tract Cancer).
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]A weekly continuous 24-h infusion therapy with 5-fluorouracil (5-FU) preceded by a 2-h infusion of calcium folinate (CA-FA) was shown to be an effective first- and secondline treatment in advanced metastatic colorectal cancer. Substitution of CA-FA by the new formulation sodium folinate (S-FA) allows the simultaneous i.v. administration of folinic acid with 5-FU in one pump.
Failure to alter the course of acute myelogenous leukemia in the rat with subcutaneous deferoxamine. [2019]Deferoxamine (DFO) is an iron chelator that is known to inhibit acute non-lymphocytic leukemia cells in vitro. To explore the possibility that this drug has cytotoxic activity in vivo, rats were inoculated with a small lethal dose (10(2] of tumor cells from the transplantable BN acute myelogenous leukemia model. Animals were then treated with one of several regimens of bolus subcutaneous DFO: 10 mg/day x 5; 20 mg/day x 5; 10 mg/day x approximately 5 weeks; or no DFO. There were no consistently significant differences in survival between any of the DFO and untreated groups. Because the short plasma half-life of DFO was thought to be a potential reason for this lack of protection, a high molecular weight polymeric conjugate of DFO that is known to provide sustained intravascular drug levels was also studied. However, hydroxyethyl starch conjugated with DFO in amounts equivalent to 100 mg free drug (intraperitoneally for 5 days) also failed to have major impact on survival. These findings suggest that it may not be possible to achieve levels of this chelating agent in vivo that are cytotoxic for this disease.
Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. [2021]Deferoxamine (DFO) is a high-affinity iron chelator approved by the Food and Drug Administration for treating iron overload. Preclinical research suggests that systemically administered DFO prevents and treats ischemic stroke damage and intracerebral hemorrhage. However, translation into human trials has been limited, probably because of difficulties with DFO administration. A noninvasive method of intranasal administration has emerged recently as a rapid way to bypass the blood-brain barrier and target therapeutic agents to the central nervous system. We report here that intranasal administration targets DFO to the brain and reduces systemic exposure, and that intranasal DFO prevents and treats stroke damage after middle cerebral artery occlusion (MCAO) in rats. A 6-mg dose of DFO resulted in significantly higher DFO concentrations in the brain (0.9-18.5 microM) at 30 min after intranasal administration than after intravenous administration (0.1-0.5 microM, p
Antileukemic effects of deferoxamine on human myeloid leukemia cell lines. [2013]Deferoxamine (DFO) possesses antiproliferative activity against mitogen-stimulated lymphocytes, several tumor cell lines, and human leukemia and neuroblastoma cells. We have investigated its effects on the human myeloid leukemia lines HL-60, HEL, and U-937. In suspension culture, DFO causes a dose-dependent inhibition of proliferation of each cell line, with maximal inhibition observed at concentrations greater than 20 microM. These effects were prevented by cotreatment with iron salts and were at least partially reversible by removal of DFO from the culture system or addition of iron before 48 h of DFO exposure. Similar results were obtained in methylcellulose cultures of leukemic cells, with complete abolition of cell aggregates at day 7 in concentrations of 20 microM DFO or higher. DFO treatment caused a dose- and time-related decrease in DNA synthesis as measured by [3H]thymidine uptake, which was also reversed by treatment with iron salts. DFO caused slight reduction in RNA synthesis and did not affect protein synthesis. DFO caused significant antiproliferative effects on three myeloid leukemia cell lines, associated with inhibition of DNA synthesis, with in vitro effects observed at concentrations attainable in vivo. Evaluation of the antileukemic properties of DFO should continue.
Intranasal deferoxamine can improve memory in healthy C57 mice, suggesting a partially non-disease-specific pathway of functional neurologic improvement. [2021]Intranasal deferoxamine (IN DFO) has been shown to decrease memory loss and have beneficial impacts across several models of neurologic disease and injury, including rodent models of Alzheimer's and Parkinson's disease.
Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. [2021]Treatment with the iron chelator, deferoxamine mesylate (DFO), improves neurological recovery in animal models of intracerebral hemorrhage (ICH). We aimed to evaluate the feasibility, safety, and tolerability of varying dose-tiers of DFO in patients with spontaneous ICH, and to determine the maximum tolerated dose to be adopted in future efficacy studies.
Deferoxamine mesylate enhancement of 67Ga tumor-to-blood ratios and tumor imaging. [2019]To improve the tumor-to-blood ratio in 67Ga tumor imaging, the effect of administration of deferoxamine mesylate (DFO) was evaluated. DFO improved 67Ga tumor-to-blood ratios in tumor-bearing rats. Administration of DFO 12 h after 67Ga injection did not decrease the concentration of radioactivity in the tumor of rats, but administration of DFO 4 h after 67Ga decreased the concentration of radioactivity in the tumor. Serum unsaturated iron binding capacity in rats was transiently increased by DFO administration, but when DFO was administered before 67Ga injection the tumor uptake showed rather decreased levels. In human studies, DFO accelerated the excretion of 67Ga from the blood, but tumor images were not necessarily improved.
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]Neural progenitor cells (NPCs) are feasible therapeutically model cells in regenerative medicine. However, a number of obstacles oppose their applications including insufficiency in differentiation protocols. These complications should be overwhelmed to obtain a significant clinical application. Deferoxamine (DFO), as a small molecule with a clinically high-affinity to chelate intracellular Iron, has been granted orphan drug status for treatment of traumatic spinal cord injury, while its neuroprotective function is not well understood. The aim of the present study is evaluating whether DFO could modulate neuronal differentiation process of NPCs. A varies concentrations of DFO were used to promote neuronal differentiation of mouse and human NPCs with different serum condition as an extracellular source of Iron. Several neural markers were assessed by RT-qPCR and Western analysis. Meanwhile β-catenin content was evaluated as key member of Wnt pathway. The maximal neuronal differentiation rate was observed when treating cells were treated with acute dosage of DFO (100 μM) for 6h in serum free condition. This treatment produced a significant increase in expression of neuronal markers and resulted in dramatically decrease in expression of glial markers. The protein content of β-catenin was also decreased by this treatment. Despite of chronic concentration of DFO, which reduced the size of EBs apparently due to G1/S arrest of cell cycle as known features of DFO. Application of acute courses of DFO increased neuronal differentiation rate of NPCs in serum free conditions. We concluded that suppression of Wnt/β-catenin pathway was induced through chelating of intracellular Iron due to DFO treatment. These findings help to understand therapeutic benefit of DFO as a neuroprotective agent.