A Phase I and Early Efficacy Study of Convection Enhanced Delivery of Irinotecan Liposome Injection Using Real Time Imaging with Gadolinium in Children with Diffuse Intrinsic Pontine Glioma
This is an open label safety study with an accelerated dose escalation design and early efficacy, single agent, multi institution trial using CED of nal-IRI in children with DIPG following standard of care focal radiotherapy. We will start with a drug concentration of 20 mg/ml and dose escalate up to 40 mg/ml concentration. We will start with a maximum volume of 2 ml of 20 mg/ml (total dose 40 mg) since the total dose of 40 mg has been found to be safe in an ongoing adult study treating adult subjects with recurrent glioblastoma via CED. In our dose escalation scheme we will allow intra-patient dose escalation by first increasing the infusion volume, and then in a second step increasing the concentration to 40 mg/ml followed by a further volume escalation. The concentration of gadoteridol (ProHance) will be 0.5 mM; both agents will be combined and co-infused via the same catheters.
Rationale for study
The overall median survival of children with DIPG is approximately 9 months, and remains unchanged despite decades of clinical trial research. The only standard of care is focal radiotherapy but essentially all children die of this disease. New therapeutic strategies are urgently needed. One of the potential reasons for failure of treatment is the blood-brain and blood-tumor barriers, which exclude potentially effective therapeutic agents. Direct delivery by convection-enhanced techniques can overcome this barrier and ensure adequate drug exposure to tumor cells. Irinotecan has been shown in pre-clinical models to be an effective cytotoxic agent in-vitro and in patient-derived brainstem xenografts, with significantly increased anti-tumor activity when given directly into tumor within the brainstem, compared to systemic delivery. Liposomal encapsulation of irinotecan (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 via convection-enhanced delivery (CED) of nal-IRI will increase progression-free and overall survival in children with newly diagnosed DIPG following standard of care radiotherapy. This trial will assess the safety and preliminary efficacy of this strategy.
To determine the safety and tolerability of repeated administration of nal-IRI co-infused with gadoteridol given by intratumoral CED in children with newly diagnosed DIPG.
To determine the clinical efficacy of repeated administration of nal-IRI given by intratumoral CED in children with newly diagnosed DIPG in the confines of a phase I and early efficacy study.
Patients must have eligibility evaluations performed within 14 days prior to registration (unless otherwise stated) and must meet all inclusion and none of the exclusion criteria. In addition, the patient must be thoroughly informed about all aspects of the study, including the study visit schedule, required evaluations and all regulatory requirements. The written informed consent must be obtained from the patient or their legal guardian prior to enrollment. The following criteria apply to all patients enrolled onto the study unless otherwise specified. The Inclusion Criteria will be applied after patients have completed radiotherapy and within the given time frame per observation as listed below. Enrollment into the trial occurs after completion of radiation therapy and if all eligibility criteria are met.
- 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.
- Treatment must begin at a minimum of 4 weeks days after, but no later than 14 weeks after, the date of the completion of radiotherapy.
- 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.
- 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.
- Age ≥ 3 years of age
- Karnofsky ≥ 50 for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (see Appendix A). 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.
- Life expectancy of greater than 12 weeks measured from the date of completion of radiotherapy.
- Corticosteroids: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration.
- Organ Function Requirements
- 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
- Adequate Renal Function Defined as:
- Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m2 or
- A serum creatinine based on age/gender as follows:
Age Maximum Serum Creatinine (mg/dL) Male Female 3 to < 6 years 0.8 0.8 6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.5 ≥ 16 years 1.5 1.5
The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.
- Adequate Liver Function Defined as:
- Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age and
- SGPT (ALT) ≤ 110 U/L and
- Serum albumin ≥ 2 g/dL
- Adequate Neurologic Function Defined as:
- Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and well controlled.
- Adequate Bone Marrow Function Defined as:
- 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.
- A legal parent/guardian or patient must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.
- Patients who are receiving any other investigational agents or other tumor-directed therapy.
- Patients with metastatic disease, including leptomeningeal or subarachnoid disseminated disease.
- Patients with tumor morphology that predicts poor coverage of the majority of the tumor. This will be determined by the study chairs. Patients with evidence of cystic changes greater than 1 cm in diameter will be excluded. These subjects should be discussed with the study chairs.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan, topotecan, gadolinium, or lipids.
- 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.
- 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 14 days of registration.
- Patients who are unable to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy. Telemedicine visits are acceptable.
- Patients with MRI or clinical evidence of uncontrolled tumor mass effect are excluded; the assessment of mass effect should be made by the study chair(s) and study neurosurgeon prior to any planned CED treatment.
- Patients with evidence of intra-tumoral hemorrhage > 5 mm maximal diameter. These subjects should be discussed with the study chair.
- 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, patients must be off for at least 10 days prior to CED infusion.
- Untreated symptomatic hydrocephalus determined by treating physician.
Important note: The eligibility criteria listed above are interpreted literally and cannot be waived.
How to Enroll
If you believe your child or patient is eligible for this trial, contact the closest participating site for more information or contact us at firstname.lastname@example.org.