human stem cell derived neurons

CED With Irinotecan Liposome Injection Using Real Time Imaging in Children With DIPG

Summary

Despite decades of clinical trial research, patient outcomes for children with diffuse intrinsic pontine glioma (DIPG) remain poor. Currently the only standard of care is focal radiation therapy, and new therapeutic strategies are urgently needed. 

One of the potential reasons for failure of treatment is the blood-brain barrier. This membrane acts like a filter, preventing harmful substances from passing from the blood into the brain, but also preventing many potentially effective therapeutic drugs from reaching the brain when they are given systemically. Convection enhanced delivery (CED) can overcome this barrier by delivering drugs directly into the brain and ensure adequate drug exposure to tumor cells. CED involves a minimally invasive surgery that allows for the direct infusion of drugs into the tumor site. Magnetic resonance (MR) contrast agents (like gadoteridol) can also be administered in combination with the drug, allowing for real-time monitoring of the drug infusion throughout the entire tumor site. 

Irinotecan is a chemotherapy drug that kills cancer cells by blocking certain enzymes needed for cell division and DNA repair. It has been shown in animal models to have significantly increased anti-tumor activity when given directly into tumors within the brainstem, compared to systemic delivery like intravenous injection. 

Other laboratory findings suggest further advantages when packaging irinotecan into liposomes, tiny fluid-filled spheres whose surface is made of specialized molecules. Liposomal encapsulation of irinotecan (a formulation called nal-IRI) increases the amount of drug that can be delivered, and because of its longer half-life, can increase drug exposure over a prolonged period of time.

The hypothesis of this study is that repeated direct delivery of nal-IRI through CED will increase progression-free and overall survival in children with newly diagnosed DIPG. This Phase I clinical trial will assess the safety and preliminary efficacy of this strategy. All eligible participants will receive the following treatment:

  • Experimental Group: nal-IRI, administered via CED

 

Inclusion Criteria
  1. Patients with newly diagnosed DIPG by MRI; defined as patients with a pontine location and diffuse involvement of at least 2/3 of the pons are eligible without histologic diagnosis. For lesions with typical imaging features, biopsy is neither encouraged nor required for eligibility. Tumors that are biopsied will be eligible if proven to be supportive of the diagnosis of a DIPG. Consensus of diagnosis by the study team must be met.
  2. Treatment must begin at a minimum of 4 weeks after but no later than 14 weeks of the date of the completion of radiotherapy.
  3. Prior Chemotherapy: Patients should be at least 30 days from last chemotherapy dose prior to start of CED infusion, with exception of antibody half-lives. For antibody therapies, at least 3 half-lives of the antibody after last dose of monoclonal antibody should have passed prior to CED infusion.
  4. Prior Radiation: Patients must have received prior treatment with focal radiotherapy as part of initial treatment for DIPG and had their last dose at least 4 weeks prior to and no later than 14 weeks from the first CED treatment with liposomal-irinotecan. Standard focal radiation therapy will include 54 to 60 Gy by external beam radiotherapy to the brainstem.
  5. Age ≥ 3 years of age
  6. Karnofsky ≥ 50 for patients > 16 years of age and Lansky ≥ 50 for patients 16 years of age and younger. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  7. Life expectancy of greater than 12 weeks measured from the date of completion of radiotherapy.
  8. Corticosteroids: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration.
  9. Organ Function Requirements
    1. Adequate Bone Marrow Function Defined as: Peripheral absolute neutrophil count (ANC) ≥1000/mm3 and platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) and normal coagulation defined as normal INR or per institutional guidelines.
    2. Adequate Renal Function Defined as:
      1. Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m2 or
      2. A maximum serum creatinine (mg/dL) based on age/gender as follows:
        1. Age 3 to <6 years: 0.8 (male), 0.8 (female)
        2. Age 6 to <10 years: 1.0 (male), 1.0 (female)
        3. Age 10 to <13 years: 1.2 (male), 1.2 (female)
        4. Age 13 to <16 years: 1.5 (male), 1.4 (female)
        5. Age ≥ 16 years: 1.7 (male), 1.4 (female)
  10. Adequate Liver Function Defined as: Bilirubin (sum of conjugated + unconjugated) less than or equal to 1.5 x upper limit of normal (ULN) for age and SGPT (ALT) less than or equal to 110 U/L. and Serum albumin ≥ 2 g/dL.
  11. Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and well controlled.
  12. The effects of irinotecan liposome injection on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and 4 months after completion of irinotecan liposome injection administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  13. Ability to understand and the willingness to sign a written informed consent document.

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Exclusion Criteria
  1. Patients who are receiving any other investigational agents or other tumor-directed therapy.
  2. Patients with metastatic disease, including leptomeningeal or subarachnoid disseminated disease.
  3. Patients with tumor morphology that predicts poor coverage of the majority of the tumor including bilateral thalamic involvement, >30% of estimated tumor volume outside the pons, or cysts that represent >50% of cross-sectional areas of the pons. Patients with evidence of cystic changes greater than 1 cm in diameter will be excluded. 
  4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan, topotecan, gadolinium, or lipids.
  5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  6. Female patients of childbearing potential must not be pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days of registration.
  7. Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.
  8. Patients with MRI or clinical evidence of uncontrolled tumor mass effect are excluded; the assessment of mass effect will be made by the study chair(s) and study neurosurgeon prior to any planned CED treatment.
  9. Patients with evidence of intra-tumoral hemorrhage > 5 mm maximal diameter. 
  10. Patients with tumor morphology that predicts poor coverage of the majority of the tumor including bilateral thalamic involvement, >30% of estimated tumor volume outside the pons, or cysts that represent >50% of cross-sectional areas of the pons. Patients with evidence of cystic changes greater than 1 cm in diameter will be excluded. 
  11. Patients must not be on enzyme-inducing anticonvulsants or other drugs that might interact with the cytochrome P450 enzyme system. If previously on an EIAED, patient must be off for at least 10 days prior to CED infusion.
  12. Untreated symptomatic hydrocephalus determined by treating physician.

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Investigator(s)

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