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

  • STATUS
    Recruiting
  • End date
    Dec 16, 2024
  • participants needed
    35
  • sponsor
    Memorial Sloan Kettering Cancer Center
Updated on 16 October 2022

Summary

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.

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.

Details
Condition Leptomeningeal Metastases
Treatment Deferoxamine (DFO)
Clinical Study IdentifierNCT05184816
SponsorMemorial Sloan Kettering Cancer Center
Last Modified on16 October 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Age ≥ 18 years on the day of consenting to study
ECOG performance status ≤ 2 and 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
For patients with both intracranial and extracranial disease progression at the time of study screening, necessitating change to their systemic tumor-directed
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
therapy
If the new systemic treatment of choice has known CNS activity at the discretion of
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
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)
Women of child-bearing potential and sexually active males must commit to the use of effective contraception while on study
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

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
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