Digoxin for the Treatment of Pediatric and Young Adult Patients with Relapsed Non-SHH, Non-WNT Medulloblastoma

Inclusion Criteria

• Patients must be age >= 12 months and < 30 years at the time of enrollment
• Patients must have relapsed non-WNT, non-SHH medulloblastoma confirmed by a College of American Pathologists (CAP)/Clinical Laboratory Improvement Amendments (CLIA) certified assay (such as nanostring or methylation) performed on tissue from diagnosis or relapse
• Patients must have received at least one prior course of chemotherapy for their medulloblastoma. They must also have received irradiation * There is no maximum number of prior therapy regimens
• Prior therapy: Therapy may not have been received more recently than the timeframes defined below: * Craniospinal radiotherapy: At least 3 months have elapsed since prior craniospinal radiotherapy (at doses >= 18 Gy) * Local radiotherapy: At least 3 months since prior local radiotherapy to primary tumor * Focal radiotherapy: At least 2 weeks since prior focal radiotherapy to symptomatic metastatic sites * Myelosuppressive chemotherapy and/or immunotherapy and/or biologics: More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas), immunotherapy, or biologics * Hematopoietic growth factor: Seven days must have elapsed since the completion of therapy with colony-stimulating factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or erythropoietin), or platelet-stimulating agents
• Patients must have recovered from any surgical procedures such as biopsy, with neurological stability for >= 7 days
• Patients must have clear residual disease, defined as tumor that is measurable in two perpendicular diameters on MRI (ie, largest tumor diameter and its largest perpendicular). The size of a measurable lesion at baseline should be at least 2 times the thickness of the slices showing the tumor (adding the interslice gap) (must be obtained within 21 days of the start of protocol therapy) * Note: Diffuse leptomeningeal disease is allowed but is not considered measurable
• Patients must have a Lansky or Karnofsky performance status score of >= 50%. Use Karnofsky for patients >= 16 years of age and Lansky for patients < 16 years of age. Patients who are unable to ambulate but who are functional in a wheelchair will be considered ambulatory for the purpose of assessing the performance score
• Absolute neutrophil count >= 750/mcL (must be obtained within 7 days of the start of protocol therapy)
• Platelets >= 75,000/mcL (must be obtained within 7 days of the start of protocol therapy)
• Total bilirubin < 3 times institutional upper limit of normal (must be obtained within 7 days of the start of protocol therapy)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 times institutional upper limit of normal (must be obtained within 7 days of the start of protocol therapy)
• Potassium within normal institutional limits, either with or without the use of potassium supplements (must be obtained within 7 days of the start of protocol therapy)
• Thyroid stimulating hormone within normal institutional limits (thyroid replacement therapy allowed if on stable dose for more than one month) (must be obtained within 7 days of the start of protocol therapy)
• Serum creatinine within normal limits based on age/gender (must be obtained within 7 days of the start of protocol therapy) OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above normal value for age (must be obtained within 7 days of the start of protocol therapy): ** 1 month to < 6 months: 0.4 mg/dL (male); 0.4 mg/dL (female) ** 1 to < 2 years: 0.6 mg/dL (male); 0.6 mg/dL (female) ** 2 to < 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female) ** 6 to < 10 years: 1 mg/dL (male); 1 mg/dL (female) ** 10 to < 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female) ** 13 to < 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female) ** >= 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female) *** The threshold creatinine values in this table were derived from the Schwartz formula for estimating glomerular filtration rate (GFR) utilizing child length and stature data published by the Centers for Disease Control (CDC)
• Patient has no evidence of Wolff-Parkinson-White syndrome or high-grade atrioventricular (AV) block (form of second-degree heart block) on screening electrocardiogram (ECG)
• Patient has no evidence of hypertrophic obstructive cardiomyopathy on screening echocardiography (echo) (must be obtained within 4 weeks of start of protocol therapy)
• Any patient that reports recent palpitations (within the last month), or concerning findings on echo or ECG must be evaluated and cleared for treatment with digoxin by a cardiologist prior to enrollment. Study principal investigator (PI) should be contacted for additional questions/concerns regarding these patients
• Patients receiving concurrent dexamethasone are eligible, provided dosage is stable or decreasing for >=7 days prior to study enrollment
• Patients must have a stable neurologic status for >=7 days prior to study enrollment. If a patient experiences neurologic decline following enrollment but prior to day 1 of cycle 1, they should be re-assessed for eligibility
• Females of childbearing potential must have a negative urine or serum pregnancy test prior to enrollment. Female patients who are lactating must agree to stop breastfeeding
• 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 and for the duration of study participation. 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
• All patients and/or their parents or legal guardians must have the ability to understand and the willingness to sign a written informed consent or assent document

Exclusion Criteria

• Participants who are receiving concurrent anticancer or any other investigational agents are ineligible
• Participants taking digoxin for any reason during treatment for initial diagnosis of medulloblastoma or relapse are ineligible. Exposure to digoxin therapy prior to initial diagnosis of medulloblastoma is allowed
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to digoxin are ineligible
• Patients with serious or inadequately controlled cardiac arrhythmias, including baseline ectopy, ventricular tachycardia, frequent premature ventricular contractions (PVCs), or symptomatic sinus bradycardia are excluded from the study
• Patients taking medications that are known to interfere with digoxin metabolism are ineligible
• Participants with uncontrolled intercurrent illness, concurrent clinically significant unrelated systemic illness (e.g. serious infection) or significant cardiac, pulmonary, hepatic, or other organ dysfunction that would compromise the patient's ability to tolerate study treatment or would likely interfere with study procedures or results are ineligible
• Participants with psychiatric illness/social situations that would limit compliance with study requirements are ineligible
• Pregnant women or women unwilling to stop breastfeeding are excluded from this study because it is unknown how pregnant women with recurrent medulloblastoma will metabolize and tolerate digoxin. There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with digoxin in this setting
• Participants who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study