A Study of Deferoxamine (DFO) in People With Leptomeningeal Metastasis

A Phase 1a/1b Trial of Intrathecal Deferoxamine for Leptomeningeal Metastases

The researchers are doing this study to find out whether deferoxamine (DFO) given intrathecally (directly into the CSF) is a safe treatment for people with leptomeningeal metastasis from solid tumor cancer. The researchers will test different doses of DFO to find the highest dose that causes few or mild side effects. When the dose is found, they will test it in future participants to see whether DFO is a safe and effective treatment for people with leptomeningeal metastasis from non-small cell lung cancer (NSCLC). They are also doing this study to see how the body absorbs, distributes, gets rid of, and responds to DFO.

Study Overview

• Status: Recruiting
• Conditions: Leptomeningeal Metastases
• Intervention / Treatment: Drug: Deferoxamine (DFO)

Detailed Description

Phase 1a

During the phase 1a arm, the MTD and PK/PD data will be evaluated in patients with LM from any solid tumor malignancy in an accelerated dose escalation fashion, with conversion to a traditional 3 + 3 dose escalation scheme at either dosing cohort 5 or when alternative criteria is met [either 1 patient experiences a DLT or 2 patients experience any grade 2 or higher nervous system disorder toxicity (except headache)]. All patients will receive IT-DFO via Ommaya reservoir 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. DLTs and new grade 2 or higher nervous system toxicities will be assessed for the first 28 days of each cohort.

Patients will undergo PK/PD assessments at the time of C1-3 doses 1 and 2 (six dosing time points) to evaluate changes iron, DFO, and ferrioxamine concentrations in the blood and CSF at each dosing cohort.

The Principal Investigator will consider the MTD determined by the dose escalation, any cumulative or delayed CNS toxicities (if present), and PK/PD data of phase 1a when determining the RP2D of phase 1b.

Phase 1b

The phase 1b dose expansion will be determined by the RP2D of the phase 1a arm, and will be restricted to patients with NSCLC. All patients will receive IT-DFO via Ommaya reservoir 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.

Patients will undergo PK/PD assessments at the time of C1-3 doses 1 and 2 (six dosing time points) to evaluate changes iron, DFO, and ferrioxamine concentrations in the blood and CSF at each dosing cohort. PK/PD assessments will no longer be required after 5 patients in phase 1b have completed all six timepoints of completed analysis.

In addition to safety and PK/PD endpoints, patients in phase 1b will also be assessed for early efficacy endpoints.

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Adrienne Boire, MD, PhD; Phone Number: 646-888-3786; Email: boirea@mskcc.org
• Study Contact Backup: Name: Jessica Wilcox, MD; Phone Number: 212-639-6767; Email: wilcoxj@mskcc.org

Study Locations

• United States
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Recruiting
      • Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)
      • Contact: Adrienne Boire, MD, PhD; Phone Number: 646-888-3786
      • Contact: Jessica Wilcox, MD; Phone Number: 212-639-6767
    • Middletown, New Jersey, United States, 07748
      • Recruiting
      • Memorial Sloan Kettering Monmouth (Limited protocol activities)
      • Contact: Jessica Wilcox, MD; Phone Number: 212-639-6767
      • Contact: Adrienne Boire, MD; Phone Number: 646-888-3786
    • Montvale, New Jersey, United States, 07645
      • Recruiting
      • Memorial Sloan Kettering Bergen (Limited Protocol Activities)
      • Contact: Adrienne Boire, MD, PhD; Phone Number: 646-888-3786
      • Contact: Jessica Wilcox, MD; Phone Number: 212-639-6767
  • New York
    • Commack, New York, United States, 11725
      • Recruiting
      • Memorial Sloan Kettering Suffolk - Commack (Limited Protocol Activities)
      • Contact: Adrienne Boire, MD, PhD; Phone Number: 646-888-3786
      • Contact: Jessica Wilcox, MD; Phone Number: 212-639-6767
    • Harrison, New York, United States, 10604
      • Recruiting
      • Memorial Sloan Kettering Westchester (Limited Protocol Activities)
      • Contact: Adrienne Boire, MD, PhD; Phone Number: 646-888-3786
      • Contact: Jessica Wilcox, MD; Phone Number: 212-639-6767
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center (All Protocol Activities)
      • Contact: Adrienne Boire, MD, PhD; Phone Number: 646-888-3786
      • Contact: Jessica Wilcox, MD; Phone Number: 212-639-6767
      • Principal Investigator: Adrienne Boire, MD, PhD
    • Uniondale, New York, United States, 11553
      • Recruiting
      • Memorial Sloan Kettering Nassau (Limited Protocol Activities)
      • Contact: Adrienne Boire, MD, PhD; Phone Number: 646-888-3786
      • Contact: Jessica Wilcox, MD; Phone Number: 212-639-6767

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years on the day of consenting to study
• ECOG performance status ≤ 2 or KPS ≥ 60.
• Life expectancy ≥ 8 weeks in the opinion of the Investigator

• LM from any solid tumor malignancy (1a) or NSCLC (1b), that is either:

  • Newly diagnosed: As evidenced by positive CSF cytology, CTC count >3.0/3.0 mL, or unequivocal radiographic evidence of LM on contrast-enhanced MRI, OR
  • Recurrent: As evidenced by unequivocal radiographic progression on contrast-enhanced MRI, the development of newly or recurrently positive CSF cytology, or a clinically-relevant rise in CSF CTCs at the discretion of the treating Investigator. There are no restrictions on the number of recurrences.

OR

• Persistent: As evidenced by any detectable disease (abnormal leptomeningeal enhancement on contrast-enhanced MRI; positive, suspicious, or atypical cytology; positive CSF CTCs; extrinsic cells on CSF cell count differential; or clinical symptoms attributed to LM) after receiving LM-directed radiation or systemic therapy. This includes patients with stable or partially responding LM who, in the opinion of the investigator, would benefit from additional LM-directed therapy.

  • Confirmation of solid tumor malignancy (phase 1a) and NSCLC primary malignancy (phase 1b) may be made by histopathologic criteria of any primary or metastatic site. For patients that have not previously undergone internal pathology review at MSKCC, a pathology report confirming the primary malignancy is sufficient. Patients with all known mutational signatures of NSCLC (EGFR, ALK, ROS1, KRAS, etc. mutant and wildtype) are allowed to enroll (phase 1b).
  • Patients can have concomitant parenchymal brain metastases at study entry as long as they do not require active treatment or have been previously treated.
  • Patients with seizure disorders, stable on appropriate antiepileptic therapies, are eligible for this trial.
  • Patients must have normal CSF flow dynamics at the clinical judgment of the treating investigator, with no obstructive hydrocephalus or ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt.
  • Patients with isolated intracranial LM progression and stable extracranial disease may enroll on trial. If this population is receiving systemic treatment that is controlling their extracranial disease, they may remain on this regimen during study enrollment provided their LM progression occurred on this regimen.
  • For patients with both intracranial and extracranial disease progression at the time of study screening, necessitating change to their systemic tumor-directed therapy:
• If the new systemic treatment of choice has known CNS activity at the discretion of the Principal Investigator, then they should be monitored on this new regimen for 21 days with confirmation of persistent LM (by neuraxial imaging and CSF reassessment) before enrolling on study.
• If the new systemic treatment of choice has no known CNS activity at the discretion of the Principal Investigator, then they may start IT-DFO concurrently with the new systemic treatment.

• Examples of systemic CNS-active treatments include but are not limited to: bevacizumab, temozolomide, carmustine, lomustine, etoposide, carboplatin, cisplatin, pemetrexed, doxorubicin, high-dose erlotinib, osimertinib, lorlatinib, lapatinib, tucatinib, capecitabine, dabrafenib, trametinib, vemurafenib, cobimetinib, ipilimumab, nivolumab, pembrolizumab, atezolizumab

  • Patients must have a functioning Ommaya reservoir prior to the first IT-DFO administration or be an appropriate surgical candidate for Ommaya reservoir placement and agree to Ommaya reservoir placement as standard of care prior to the first IT-DFO administration.
  • Adequate bone marrow and organ function as demonstrated by:
• White blood cell (WBC) count ≥ 2.5 K/mcL
• Absolute neutrophil count (ANC) ≥ 1.0 K/mcL
• Platelet count ≥ 50 K/mcL at least 7 days from last platelet transfusion
• Hemoglobin (Hgb) ≥ 8 g/dL
• Serum creatinine ≤ 1.5 times the upper limit of normal (ULN)
• Serum bilirubin ≤ 1.5 times the ULN; or total bilirubin ≤ 3 times the ULN with direct bilirubin within the normal range in patients with well documented Gilbert Disease

• Serum alanine aminotransferase (ALT) and aspartate aminotransaminase (AST) ≤ 3 times the ULN, unless known hepatic disease wherein may be ≤ 5 times the ULN is acceptable.

  • Women of child-bearing potential and sexually active males must commit to the use of effective contraception while on study.

Exclusion Criteria:

• Any CNS-directed irradiation within 7 days of first dose of IT-DFO.
• Patients receiving other therapy (either intrathecal or systemic) designed to treat their LM, with ongoing acceptable control of their LM.
• Any contraindication to gadolinium-enhanced MRI
• Use of any systemic iron chelators within 4 weeks of first dose
• Use of ascorbic acid or prochlorperazine within 2 weeks of first dose
• Patients are not allowed to receive whole-brain radiation therapy or craniospinal radiation therapy during study enrollment.
• Patients must not have any physical and/or psychiatric illness that would interfere with their compliance and ability to tolerate treatment as per the protocol.
• Women may not be pregnant or breastfeeding
• Known hypersensitivity or allergic reaction to iron chelating agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Deferoxamine (DFO); 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 non-small cell lung cancer (NSCLC). Study objectives will include safety (1a/1b), pharmacokinetics (PK) and pharmacodynamics (PD) of IT-DFO (1a/1b), and preliminary anti-tumoral efficacy in patients with LM from NSCLC (1b).

Drug: Deferoxamine (DFO); The accelerated single-patient dose escalation will apply to dosing cohorts 1 through 4 (10mg, 30mg, 60mg, 100mg) and will convert to a 3+3 dose escalation for cohorts 5 through 9 (150mg, 210mg, 280mg, 372mg, 495mg).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of dose-limiting toxicities (DLTs) during Phase Ia (Primary safety endpoint during dose-finding phase)	Patients are considered evaluable for the primary safety endpoint of DLT if they receive at least one full cycle (twice weekly dosing for 4 weeks) without a DLT or if they experience a DLT at any time during the first cycle of IT-DFO. Per CTCAE version 5.0	1 year
Frequency of dose-limiting toxicities (DLTs) during Phase Ib (RP2D of IT-DFO in patients with LM from NSCLC)	Per CTCAE version 5.0	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
objective response rate (ORR)	LM objective response rate (ORR) is defined as the proportion of patients with at least one objective response in LM, using a combined approach taking into account radiographic, neurologic and cytologic assessments based on RANO-LM.	1 year

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: Center for Experimental Therapeutics; F.M. KIRBY FOUNDATION
• Investigators: Principal Investigator: Adrienne Boire, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

Helpful Links

• Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2021
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: December 22, 2021
• First Submitted That Met QC Criteria: December 22, 2021
• First Posted (Actual): January 11, 2022

Study Record Updates

• Last Update Posted (Estimated): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: persistent; recurrent; Deferoxamine (DFO); 21-378
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neoplasms; Neoplasms by Site; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Meningeal Neoplasms; Neoplasm Metastasis; Meningeal Carcinomatosis; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Siderophores; Deferoxamine
• Other Study ID Numbers: 21-378

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No