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

Status: Active

Description

This phase I trial studies the best dose and side effects of ribociclib, gemcitabine hydrochloride, trametinib, and sonidegib in treating children and young adults with brain cancers that have come back or do not respond to treatment. Ribociclib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride and sonidegib, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ribociclib, gemcitabine hydrochloride, trametinib, and sonidegib may work better at treating brain cancers.

Eligibility Criteria

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 screening
  • STRATUM A: Participants must have received their last dose of anticancer therapy (including experimental) at least 4 weeks prior to study enrollment
  • 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
  • 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 at the time of study enrollment; 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 >= 16kg and < 32kg * For enrollment on dose level 0B must have a weight >= 32kg and BSA >= 0.55m^2 * For enrollment on dose level 1, must have a weight >= 16kg and BSA >= 0.55m^2 * For enrollment on dose level 2, must have a weight >= 16kg and BSA >= 0.63m^2 * For enrollment on dose levels 3 or 4A, must have a weight >= 16kg * For enrollment on dose levels 4B or 5, must have a weight >= 20kg and =< 106kg
  • STRATUM B: Participants must have received their last dose of anticancer therapy (including experimental) at least 4 weeks prior to study enrollment
  • 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
  • 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; 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
  • 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
  • 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; 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

Locations & Contacts

Tennessee

Memphis
St. Jude Children's Research Hospital
Status: Active
Contact: Giles W. Robinson
Phone: 901-595-3300
Email: SJDAWN@stjude.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability and estimate the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) of combination treatment with ribociclib and gemcitabine in patients with recurrent Group 3 and Group 4 medulloblastoma and recurrent ependymoma. (Stratum A)

II. To characterize the pharmacokinetics of ribociclib and gemcitabine. (Stratum A)

III. To determine the safety and tolerability and estimate the MTD/RP2D of combination treatment with ribociclib and trametinib in patients with recurrent or refractory central nervous system (CNS) tumors (excluding low grade glioma and diffuse intrinsic pontine glioma). (Stratum B)

IV. To characterize the pharmacokinetics of ribociclib and trametinib. (Stratum B)

V. To determine the safety and tolerability and estimate the MTD/RP2D of combination treatment with ribociclib and sonidegib in patients with recurrent sonic hedgehog (SHH) medulloblastoma. (Stratum C)

VI. To characterize the pharmacokinetics of ribociclib and sonidegib. (Stratum C)

SECONDARY OBJECTIVES:

I. To estimate the rate and duration of objective response and progression free survival (PFS) of ribociclib and gemcitabine. (Stratum A)

II. To estimate the rate and duration of objective response and progression free survival (PFS) of ribociclib and trametinib. (Stratum B)

III. To estimate the rate and duration of objective response and progression free survival (PFS) of ribociclib and sonidegib. (Stratum C)

EXPLORATORY OBJECTIVES:

I. To perform detailed molecular analysis of the tumor samples. (Strata A, B & C)

II. To molecularly compare tumor samples acquired at diagnosis to relapsed tumor samples, when available. (Strata A, B & C)

III. To explore, through molecular analysis, any correlation between clinical outcome and molecular characteristics. (Strata A, B & C)

IV. To explore the association between molecular features, patterns of recurrence, and tumor characteristics by magnetic resonance imaging (MRI). (Strata A, B & C)

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 3 strata.

STRATUM A: Patients receive ribociclib orally (PO) once daily (QD) on days -1 to 21 of cycle 1 and on days 1-21 of the subsequent cycles, and gemcitabine hydrochloride intravenously (IV) over 30-60 minutes on days 1 and 15. Cycles repeat every 28 days for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity.

STRATUM B: Patients receive trametinib PO QD on days 1-14, and ribociclib PO QD on days 8-21. On cycle 1 day 2 only the trametinib dose will be withheld. A total of 13 doses of trametinib will be administered in cycle 1. Cycles repeat every 28 days for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity.

STRATUM C: Patients receive ribociclib PO QD on days -1 and 1- 21 of cycle 1 and on days 1-21 of the subsequent cycles, and sonidegib PO QD on days 1-28. Cycles repeat every 28 days for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 1 year.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
St. Jude Children's Research Hospital

Principal Investigator
Giles W. Robinson

Trial IDs

Primary ID SJDAWN
Secondary IDs NCI-2018-00284
Clinicaltrials.gov ID NCT03434262