Medulloblastoma, Medulloblastoma, Childhood, Medulloblastoma Recurrent
Conditions
Brief summary
This is a Phase 1/Phase 2 study assessing liothyronine (L-T3) immunotherapy and in combination with standard chemotherapy (bevacizumab, irinotecan and temozolomide (BIT)) in children and young adults with medulloblastoma that is relapsed or progressive after standard upfront therapy.
Detailed description
OUTLINE: This is an intra-patient dose escalation (Phase 1 (Cohort 1)) followed by a Phase 2 (Cohort 2) study. Cohort 1: Children and young adults with relapsed or progressive disease following standard upfront therapy (including craniospinal radiation or high dose chemotherapy with autologous stem cell rescue). evaluating the safety and efficacy of combination L-T3 with BIT. Cohort 2: Children and young adults with medulloblastoma and CSF cell-free deoxyribonucleic acid (cf-DNA) positivity without radiographic disease progression/recurrence following standard upfront therapy. This is a Phase 2 study to evaluate clearance of Circulating free DNA (cfDNA) positive disease in CSF in response to L-T3 monotherapy at the RP2D (established as part of Cohort 1; Phase 1) as single agent. Participants may continue therapy for up to 12 cycles if there is no evidence of unacceptable toxicity, disease progression, or withdrawal of consent. For participants that are benefiting from therapy, they may continue L-T3 monotherapy for one additional year (24 cycles total therapy). Treatment beyond that specified in the protocol should be discussed with the study chairs. Duration of Follow up Participants will enter follow up after the 30-day toxicity period. Follow-up procedures are to be captured under the Pediatric NeuroOncology Consortium (PNOC) COMP protocol with the exception of protocol defined follow up procedures. Participants will be followed under the PNOC COMP protocol until death or withdrawal from study. The study will complete enrollment within 5 years from the time the study opens to accrual (including 3 years for enrollment and 2 years of long term follow up).
Interventions
Given orally (PO)
DRUGBevacizumab
Given IV
DRUGIrinotecan
Given IV
DRUGTemozolomide (TMZ)
Given PO
Sponsors
Sabine Mueller, MD, PhD
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
1. Phase 1 and Phase 2, Cohort 1: Participants must have histologically confirmed medulloblastoma that is relapsed/progressive following standard upfront therapy. Tissue confirmation of medulloblastoma diagnosis is required at diagnosis and not required at the time of relapse for entry into the study. 2. Phase 2, Cohort 2: Participants must have cerebrospinal fluid (CSF) with cell-free deoxyribonucleic acid (cf-DNA) + assessed in a Chemiluminescent immunoassay (CLIA)-certified or protocol-approved laboratory. After entry into the study, another CSF sample will be collected and analyzed centrally prior to initiation of protocol therapy to verify cf-DNA positivity. 3. Evidence of Disease: Phase 1 and Phase 2, Cohort 1: Participants may have either Measurable or Evaluable Disease Measurable Disease: Participants must have clear residual disease at the time of enrollment, defined as tumor that is measurable in two perpendicular dimensions on MRI Evaluable Disease: Diffuse leptomeningeal disease OR clear MRI evidence of disease that may not be measurable in two perpendicular dimensions. Phase 2, Cohort 2: For cf-DNA positive cohort: Participants are not required to have measurable or evaluable disease but must have cf-DNA positivity in a CLIA-certified or protocol-approved laboratory, as above. 4. Prior Therapy: Participants must have received standard upfront therapy for medulloblastoma (either with craniospinal radiation or high dose chemotherapy and autologous stem cell rescue. If other therapy utilized, must be discussed with study chairs prior to participation). Participants for Phase 1 and Phase 2 cohort 1 may have received further chemotherapy and/or radiation therapy beyond standard upfront therapy prior to trial enrollment. Participants within the Phase 2 cohort 1 must have experienced at least one, and at most, two relapses prior to study enrollment. 5. Age 1-25 years old. 6. Performance Score: Karnofsky ≥ 50 for participants \> 16 years of age and Lansky ≥ 50 for participants ≤16 years of age (See Appendix A). Participants 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. For those participants currently treated with levothyroxine (Synthroid) they must have stable dosing for a minimum of 3 months prior to enrollment. 8. Organ Function Requirements 1. Peripheral absolute neutrophil count (ANC) ≥ 1000/cubic millimeters (mm3) 2. Platelet count ≥ 75,000/microliter (uL) (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). 3. A serum creatinine \< 1.5 institutional/reference range upper Limit normal (ULN) based on age and gender 4. Total bilirubin ≤ 3 x upper limit of normal (ULN); in presence of Gilbert's syndrome, total bilirubin ≤ 6 x ULN or direct bilirubin ≤ 3 x ULN * Alanine aminotransferase (ALT) ≤ 5 x upper limit of normal (ULN) * Aspartate aminotransferase (AST) ≤ 5 x ULN. 3.3.7.4 Adequate Neurologic Function Defined as: * Participants with seizure disorder may be enrolled if well controlled. Participants on non-enzyme inducing anticonvulsants may be excluded pending interaction(s) with study drug. 3.3.7.5 Adequate Cardiac Function Defined as: * Normal left ventricular systolic function on baseline transthoracic echocardiogram (TTE) * Normal left ventricular systolic function is defined as left ventricular ejection fraction (LVEF) \>55% or shortening fraction (SF) \>28%. AND * No clinically significant arrhythmia on baseline ECG (sinus arrhythmia, sinus tachycardia, sinus bradycardia, early repolarization and 1st degree atrioventricular block when partial response (PR) interval \< 300 millisecond (ms) are not considered clinically significant arrhythmias). * In addition, the following ECG findings are not considered clinically significant in the setting of a normal echocardiogram: * Left axis deviation * Left atrial enlargement * Right atrial enlargement * Possible left ventricular hypertrophy * Possible right ventricular hypertrophy * Non-specific T wave abnormality 3.3.7.6 For the Phase 1 cohort, normal adrenal axis function is required. For those participants in the Phase 2 cohort, must have controlled adrenal insufficiency \>3 months (no change in steroid replacement or stress dose plan for at least 3 months). * Normal adrenal axis function as defined as: * Morning (AM) cortisol \>11mcg/deciliter (dL) * If AM cortisol is \<11 microgram (mcg)/dL, cosyntropin stimulation test with rise to \>18 9. Endocrine conditions: Participants with diabetes insipidus, diabetes melitus, or being treated with levothyroxine, must have stable dosing and control for minimum of 3 months prior to enrollment 10. For Cohort 1 only: participants must have recovered from any surgical procedure before enrolling on this study (see below for examples of major, intermediate, and minor surgical procedures): 1. Participants with a major surgical procedure within 28 days prior to enrollment should be excluded. 2. Participants with an intermediate surgical procedure within 14 days prior to enrollment should be excluded. 3. For minor surgical procedures (including Broviac line or infusaport placement), participants should not receive the first planned dose of bevacizumab until the wound is healed and at least 7 days have elapsed. 4. There should be no anticipation of need for major surgical procedures during the course of the study. 11. The effects of L-T3 with chemotherapy on the developing human fetus are unknown. For this reason and because chemotherapy agents as well as other therapeutic agents used in this trial are known to be teratogenic, 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 L-T3 and chemotherapy 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. 12. Participants must be enroll on PNOC COMP if PNOC COMP is open to accrual at the enrolling institution. 13. A legal parent/guardian or participant must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.
Exclusion criteria
1. For Cohort 1 only: participants who have previously been treated with BIT in combination. Treatment with individual bevacizumab, irinotecan or TMZ is not an
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants experienced an Adverse Event | Up to 28 days | Proportion of participants with adverse events of L-T3 as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0) |
| Proportion of participants who experience dose-limiting toxicity (DLT) (Dose Escalation) | Up to 28 days | The DLT evaluable analysis set includes all participants in the dose-finding part of the study who have received the target doses of L-T3, and who have either experienced a DLT or were followed for the full DLT evaluation period. DLT is defined as L-T3-related toxicity at a frequency ≥33% in any treatment arm. |
| Maximum Tolerated Dose (MTD) (Dose Escalation) | Up to 28 days | The DLT evaluable analysis set includes all participants in the dose-finding part of the study who have received the target doses of L-T3, and who have either experienced a DLT or were followed for the full DLT evaluation period. The MTD is defined as the dose level given for 14 days which ≤ 1/6 participants experience a DLT. |
| Percentage Progressive Free Survival (PFS) at month 9 | up to 9 months | Cohort 1 Phase 2, PFS at 9 months is defined as the proportion of patients alive and progression-free 9 months from start of treatment. Any patient lost-to-follow-up prior to 9 months will be considered an event (i.e., progression/death) for the purposes of the analysis. |
| Percentage of cf-DNA clearance | Up to 30 days after last dose of L-T3. | Participants in Cohort 2 Phase 2 will be assessed in two serial measurements of at least one month apart to determine cf-DNA clearance in cerebrospinal fluid (CSF). Percentage of participants with cf-DNA clearance will be reported. |
Countries
United States
Contacts
CONTACTKelly Hitchner
PRINCIPAL_INVESTIGATORSabine Mueller
University of California, San Francisco
Outcome results
None listed