Ribociclib, Gemcitabine Hydrochloride, Trametinib, and Sonidegib in Treating Patients with Refractory or Recurrent Brain Cancers

Inclusion Criteria

• SCREENING PHASE INCLUSION CRITERIA
• Participants with recurrent, progressive, or refractory brain tumors
• Age >= 1 year and < 25 years at the time of screening; exception: participants with recurrent, progressive, or refractory medulloblastoma and are >= 1 and < 40 years of age at the time of study screening are eligible for screening
• Participants and/or guardian have the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines
• STRATUM A: Participants with recurrent, progressive, or refractory non-WNT non-SHH (NWNS) medulloblastoma or ependymoma as confirmed through central pathology review
• STRATUM A: Evaluable disease, as defined as meeting any of the following: * Patients who have measurable disease * Patients with radiologically discernible but non-measurable lesions (i.e. leptomeningeal disease) * Patients with cerebrospinal fluid (CSF) positive disease
• STRATUM A: Age >= 1 year and < 25 years at the time of enrollment
• STRATUM A: Participants must have received their last dose of anticancer therapy (including experimental) at least 4 weeks prior to study enrollment * Note: Participants must have relapsed with recurrent, progressive or refractory disease on or after any prior anticancer therapy
• STRATUM A: Participants must have had their last fraction of radiation at least 4 weeks prior to study enrollment; participants who received radiation therapy for palliation must have had their last fraction of radiation at least 2 weeks prior to study enrollment * Note: Participants must have relapsed with recurrent, progressive or refractory disease after any prior radiation therapy that is not considered palliative * Note: Palliative radiation therapy is defined as local small port radiation therapy (RT) to alleviate and/or palliate symptoms; (craniospinal irradiation [CSI], whole brain RT, large field/port RT, or large field/port multilevel spinal RT will not be considered palliative at any dose)
• STRATUM A: Participants who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to study enrollment with no plans for escalation
• STRATUM A: Participants who are receiving known strong inducers and/or strong inhibitors of CYP3A4/5, drugs that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5, and medications that carry a known risk for QT prolongation must discontinue these drugs at least 7 days prior to study enrollment
• STRATUM A: Participants must discontinue herbal preparations, herbal medication, and dietary supplements, with the exception of multivitamins, at least 7 days prior to study enrollment
• STRATUM A: Participants must have a Lansky (=< 16 years) or Karnofsky (> 16 years) score of at least 50 and, in the opinion of the investigator, a minimum life expectancy of at least 6 weeks at the time of study enrollment * Note: 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
• STRATUM A: Absolute neutrophil count (ANC) >= 1000/mm^3 without growth factor support within 7 days of the test
• STRATUM A: Platelet count >= 50,000/mm^3 without support of a platelet transfusion within 7 days of the test
• STRATUM A: Hemoglobin >= 8.0 g/dL without support of a blood transfusion within 7 days of the test
• STRATUM A: Creatinine clearance >= 70 mL/min/1.73 m^2 or serum creatinine =< the maximum serum creatinine (mg/dL) based on age/gender as listed below: * 3 to < 6 years: 0.8 (male and female) * 6 to < 10 years: 1 (male and female) * 10 to < 13 years: 1.2 (male and female) * 13 to < 16 years: 1.5 (male), 1.4 (female) * >= 16 years: 1.7 (male), 1.4 (female)
• STRATUM A: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN); for the purposes of eligibility the ULN of ALT and AST is 45 U/L
• STRATUM A: Total bilirubin =< ULN or if > ULN then direct bilirubin =< 1.5 x ULN
• STRATUM A: Female participants of childbearing potential must have a negative pregnancy test at the time of SJDAWN study enrollment and be willing to use a highly effective method of contraception throughout the study and for 16 weeks after discontinuation of the study drug
• STRATUM A: Male participants of child fathering potential must be willing to use medically acceptable form of contraception during treatment and for 16 weeks after stopping treatment
• STRATUM A: Participant must be able to swallow medication; it is acceptable to administer medication via a gastrostomy tube (g-tube) if participant has a g-tube; it is not acceptable to place a g-tube for the purpose of delivering study medication
• STRATUM A: Participants and/or guardian have the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines
• STRATUM B: Participants with recurrent, progressive, or refractory CNS tumors as confirmed through central pathology review
• STRATUM B: Evaluable disease, as defined as meeting any of the following: * Patients who have measurable disease * Patients with radiologically discernible but non-measurable lesions (i.e. leptomeningeal disease) * Patients with CSF positive disease
• STRATUM B: Age >= 1 year and < 25 years at the time of study enrollment
• STRATUM B: Must meet the following weight and body surface area (BSA) restrictions: * For enrollment on dose level 0A, must have a weight >= 16 kg and < 32 kg * For enrollment on dose level 0B must have a weight >= 32 kg and BSA >= 0.55 m^2 * For enrollment on dose level 1, must have a weight >= 16 kg and BSA >= 0.55 m^2 * For enrollment on dose level 2, must have a weight >= 16 kg and BSA >= 0.63 m^2 * For enrollment on dose levels 3 or 4A, must have a weight >= 16 kg * For enrollment on dose levels 4B or 5, must have a weight >= 20 kg and =< 106 kg
• STRATUM B: Participants must have received their last dose of anticancer therapy (including experimental) at least 4 weeks prior to study enrollment * Note: Participants must have relapsed with recurrent, progressive or refractory disease on or after any prior anticancer therapy
• STRATUM B: Participants must have had their last fraction of radiation at least 4 weeks prior to study enrollment; participants who received radiation therapy for palliation must have had their last fraction of radiation at least 2 weeks prior to study enrollment * Note: Participants must have relapsed with recurrent, progressive or refractory disease after any prior radiation therapy that is not considered palliative * Note: Palliative radiation therapy is defined as local small port RT to alleviate and/or palliate symptoms. (CSI, whole brain RT, large field/port RT, or large field/port multilevel spinal RT will not be considered palliative at any dose.)
• STRATUM B: Participants who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to study enrollment with no plans for escalation
• STRATUM B: Participants who are receiving known strong inducers and/or strong inhibitors of CYP3A4/5, drugs that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5, and medications that carry a known risk for QT prolongation must discontinue there drugs at least 7 days prior to study enrollment
• STRATUM B: Participants must discontinue herbal preparations, herbal medication, and dietary supplements, with the exception of multivitamins, at least 7 days prior to study enrollment
• STRATUM B: Participants must have a Lansky (=< 16 years) or Karnofsky (> 16 years) score of at least 50 at the time of study enrollment and, in the opinion of the investigator, a minimum life expectancy of at least 6 weeks at the time of study enrollment * Note: 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
• STRATUM B: ANC >= to 1000/mm^3 without growth factor support within 7 days of the test
• STRATUM B: Platelet count >= 50,000/mm^3 without support of a platelet transfusion within 7 days of the test
• STRATUM B: Hemoglobin >= 8.0 g/dL without support of a blood transfusion within 7 days of the test
• STRATUM B: Creatinine clearance >= 70 mL/min/1.73 m^2 or serum creatinine =< the maximum serum creatinine (mg/dL) based on age/gender as listed below: * 3 to < 6 years: 0.8 (male and female) * 6 to < 10 years: 1 (male and female) * 10 to < 13 years: 1.2 (male and female) * 13 to < 16 years: 1.5 (male), 1.4 (female) * >= 16 years: 1.7 (male), 1.4 (female)
• STRATUM B: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN; for the purposes of eligibility the ULN of ALT and AST is 45 U/L
• STRATUM B: Total bilirubin =< ULN; or if > ULN then direct bilirubin =< 1.5 x ULN
• STRATUM B: Female participants of childbearing potential must have a negative pregnancy test at the time of SJDAWN study enrollment and be willing to use a highly effective method of contraception throughout the study and for 16 weeks after discontinuation of the study drug
• STRATUM B: Male participants of child fathering potential must be willing to use medically acceptable form of contraception during treatment and for 16 weeks after stopping treatment
• STRATUM B: Participant must be able to swallow medication; it is acceptable to administer medication via a g-tube if participant has a g-tube; it is not acceptable to place a g-tube for the purpose of delivering study medication
• STRATUM B: Participants and/or guardian have the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines
• STRATUM C: Participants with recurrent, progressive, or refractory SHH Medulloblastoma and presence of either a or b as confirmed by central pathology review of the tumor specimen: a) copy number loss of 9q b) PTCH1 mutation
• STRATUM C: Evaluable disease, as defined as meeting any of the following: * Patients who have measurable disease * Patients with radiologically discernible but non-measurable lesions (i.e. leptomeningeal disease) * Patients with CSF positive disease
• STRATUM C: Age >= 10 years and < 40 years at the time of study enrollment
• STRATUM C: Participant must be skeletally mature as defined as females with a bone age >= 15 years (180 months) and males with a bone age >= 17 years (204 months). This includes participants that are within 2 standard deviations of this value (i.e. if standard deviation [SD] = 11 months on bone age; then a male patient who has a bone age of 182 months would be eligible; or a female patient with a bone age of 158 months)
• STRATUM C: Participants must have received their last dose of anticancer therapy (including experimental) at least 4 weeks prior to study enrollment * Note: Participants must have relapsed with recurrent, progressive or refractory disease on or after any prior anticancer therapy
• STRATUM C: Participants must have had their last fraction of radiation at least 4 weeks prior to study enrollment; participants who received radiation therapy for palliation must have had their last fraction of radiation at least 2 weeks prior to study enrollment * Note: Participants must have relapsed with recurrent, progressive or refractory disease after any prior radiation therapy that is not considered palliative * Note: Palliative radiation therapy is defined as local small port RT to alleviate and/or palliate symptoms. (CSI, whole brain RT, large field/port RT, or large field/port multilevel spinal RT will not be considered palliative at any dose.)
• STRATUM C: Participants previously treated with a smoothened inhibitor must have received their last dose > 6 months prior to study enrollment
• STRATUM C: Participants who are receiving corticosteroids must be on a stable or decreasing dose for at least 1 week prior to study enrollment with no plans for escalation
• STRATUM C: Participants who are receiving known strong inducers and/or strong inhibitors of CYP3A4/5, drugs that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5, and medications that carry a known risk for QT prolongation must discontinue there drugs at least 7 days prior to study enrollment
• STRATUM C: Participants must discontinue herbal preparations, herbal medication, and dietary supplements, with the exception of multivitamins, at least 7 days prior to study enrollment
• STRATUM C: Participants must have a Lansky (=< 16 years) or Karnofsky (> 16 years) score of at least 50 at the time of study enrollment and, in the opinion of the investigator, a minimum life expectancy of at least 6 weeks at the time of study enrollment * Note: 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
• STRATUM C: ANC >= 1,000/mm^3 without growth factor support within 7 days of the test
• STRATUM C: Platelet count >= 50,000/mm^3 without support of a platelet transfusion within 7 days of the test
• STRATUM C: Hemoglobin >= 8.0 g/dL without support of a blood transfusion within 7 days of the test
• STRATUM C: Creatinine clearance >= 70 mL/min/1.73 m^2 or serum creatinine =< the maximum serum creatinine (mg/dL) based on age/gender as listed below: * 3 to < 6 years: 0.8 (male and female) * 6 to < 10 years: 1 (male and female) * 10 to < 13 years: 1.2 (male and female) * 13 to < 16 years: 1.5 (male), 1.4 (female) * >= 16 years: 1.7 (male), 1.4 (female)
• STRATUM C: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN; for the purposes of eligibility, the ULN of ALT and AST is 45 U/L
• STRATUM C: Total bilirubin =< ULN; or if > ULN then direct bilirubin =< 1.5 x ULN
• STRATUM C: Female participants of childbearing potential must have a negative pregnancy test at the time of SJDAWN study enrollment and be willing to use a highly effective method of contraception throughout the study and for 8 months after discontinuation of the study drug
• STRATUM C: Male participants of child fathering potential must be willing to use medically acceptable form of contraception during treatment and for 8 months after stopping treatment
• STRATUM C: Participant must be able to swallow medication; it is acceptable to administer medication via a g-tube if participant has a g-tube; it is not acceptable to place a g-tube for the purpose of delivering study medication
• STRATUM C: Participants and/or guardian have the ability to understand and the willingness to sign a written informed consent document according to institutional guidelines

Exclusion Criteria

• SCREENING PHASE EXCLUSION CRITERIA
• Participants with a diagnosis of recurrent, progressive, or refractory low grade glioma (LGG)
• Previous exposure to a CDK4/6 inhibitor (palbociclib, abemaciclib, or ribociclib)
• Participants with a history of clinically significant, uncontrolled heart disease and/or repolarization abnormalities
• Participants with any history of corrected QT (QTc) prolongation (i.e. QTc interval of > 450 msec)
• STRATUM A: Participants with subependymoma or myxopapillary ependymoma
• STRATUM A: Participants receiving any other investigational agents
• STRATUM A: Participants with other clinically significant medical disorders (serious infections or significant cardiac, pulmonary, hepatic, psychiatric, gastrointestinal [GI] disease, or other organ dysfunction) that in the investigator’s judgment could compromise their ability to tolerate or absorb protocol therapy or would interfere with the study procedures or results
• STRATUM A: Female participants who are breastfeeding a child
• STRATUM A: Participants with QTc interval of > 450 msec on screening electrocardiogram (ECG)
• STRATUM A: Participants with a pathogenic somatic or known germline retinoblastoma (RB1) gene mutation
• STRATUM B: Participants with low grade glioma (LGG) or diffuse intrinsic pontine glioma (DIPG)
• STRATUM B: Participants receiving any other investigational agents
• STRATUM B: Participants with other clinically significant medical disorders (serious infections or significant cardiac, pulmonary, hepatic, psychiatric, GI disease, or other organ dysfunction) that in the investigator’s judgment could compromise their ability to tolerate or absorb protocol therapy or would interfere with the study procedures or results
• STRATUM B: Female participants who are breastfeeding a child
• STRATUM B: Participants with QTc interval of > 450 msec on screening ECG
• STRATUM B: Participants with abnormal left ventricular ejection fraction (LVEF) on screening, defined as > 10% below lower limit of normal
• STRATUM B: Participants with a pathogenic somatic or known germline retinoblastoma (RB1) gene mutation
• STRATUM B: Participants with retinal vein occlusion (RVO)
• STRATUM B: Previous exposure to a MEK inhibitor (i.e., trametinib, selumetinib)
• STRATUM C: Participants receiving any other investigational agents
• STRATUM C: Participants with other clinically significant medical disorders (serious infections or significant cardiac, pulmonary, hepatic, psychiatric, GI disease, or other organ dysfunction) that in the investigator’s judgment could compromise their ability to tolerate or absorb protocol therapy or would interfere with the study procedures or results
• STRATUM C: Participants with QTc interval of > 450 msec on screening ECG
• STRATUM C: Female participants who are breastfeeding a child
• STRATUM C: Participants with a pathogenic somatic or known germline retinoblastoma (RB1) gene mutation