A Phase 1 interventional study of Gemcitabine and ribociclib in Anaplastic Astrocytoma, Anaplastic Ependymoma and Anaplastic Ganglioglioma, sponsored by St. Jude Children's Research Hospital. Completed at 1 site in United States. Open to participants aged 1 Year to 39 Years. Per ClinicalTrials.gov, last updated 2024-05-31.
Sponsored by St. Jude Children's Research Hospital · Phase 1, Interventional, and Treatment
Approximately 90% of children with malignant brain tumors that have recurred or relapsed after receiving conventional therapy will die of disease. Despite this terrible and frustrating outcome, continued treatment of this population remains fundamental to improving cure rates. Studying this relapsed population will help unearth clues to why conventional therapy fails and how cancers continue to resist modern advances. Moreover, improvements in the treatment of this relapsed population will lead to improvements in upfront therapy and reduce the chance of relapse for all. Novel therapy and, more importantly, novel approaches are sorely needed. This trial proposes a new approach that evaluates rational combination therapies of novel agents based on tumor type and molecular characteristics of these diseases. The investigators hypothesize that the use of two predictably active drugs (a doublet) will increase the chance of clinical efficacy. The purpose of this trial is to perform a limited dose escalation study of multiple doublets to evaluate the safety and tolerability of these combinations followed by a small expansion cohort to detect preliminary efficacy. In addition, a more extensive and robust molecular analysis of all the participant samples will be performed as part of the trial such that we can refine the molecular classification and better inform on potential response to therapy. In this manner the tolerability of combinations can be evaluated on a small but relevant population and the chance of detecting antitumor activity is potentially increased. Furthermore, the goal of the complementary molecular characterization will be to eventually match the therapy with better predictive biomarkers.
PRIMARY OBJECTIVES:
SECONDARY OBJECTIVE:
Patients will be stratified by the molecular and histologic characteristics of their tumor to one of three treatment strata.
STRATUM A:
STRATUM B:
STRATUM C:
The rolling 6 design will be used separately in each stratum to estimate the MTD or RP2D and determine the dose-limiting toxicity (DLT) of the combination of escalating doses. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity. Stratum A participants may continue therapy past 24 months in absence of disease progression or unacceptable toxicity.
Patients will receive doublet therapy in cycles of 28 days. The dose-limiting toxicity (DLT)-evaluation period will consist of the first cycle (i.e. first 4 weeks of therapy). Research participants will be evaluated at least once a week during the DLT-evaluation period and at regular intervals thereafter. Standard (e.g., physical exam, blood tests, and disease evaluations) tests will be obtained at regular intervals. Research-associated evaluations (e.g., pharmacokinetic studies, etc.) will also be obtained during therapy. Treatment may be continued for up to 2 years in the absence of disease progression or unacceptable toxicity. Stratum A participants may continue past 2 years in the absence of disease progression or unacceptable toxicity.
2,132 studies on the registry are indexed under Glioblastoma; 464 are open to participants now.
This study's enrollment of 68 is above the median of 36 across 1,753 interventional studies indexed under Glioblastoma.
Browse Glioblastoma studies →St. Jude Children's Research Hospital is the lead sponsor of 440 studies on the registry; 102 are open to participants now.
Of its 61 completed or terminated interventional studies of FDA-regulated products, 37 (61%) have results posted.
Compared within Glioblastoma, this study's primary condition as ClinicalTrials.gg classifies it; the registry's first condition term is Astrocytoma. The counts are of registry records indexed under each term, refreshed daily. How we classify →
Potential participants will first be screened using the screening inclusion/exclusion shown below. If they meet the requirements of the screening phase, they will then be evaluated for enrollment based on the overall study's inclusion criteria as well as the stratum-specific inclusion/exclusion criteria for the applicable stratum, all of which are shown below.
SCREENING INCLUSION CRITERIA - ALL PARTICIPANTS:
SCREENING EXCLUSION CRITERIA - ALL PARTICIPANTS:
Participants who meet the requirements of the screening phase will then be evaluated for enrollment based on the overall study's inclusion criteria as well as the stratum-specific inclusion/exclusion criteria for the applicable stratum, all of which are shown below.
INCLUSION CRITERIA - OVERALL STUDY - ALL PARTICIPANTS:
Evaluable disease, as defined as meeting any of the following:
Participants must have received their last dose of anticancer therapy (including experimental) at least 4 weeks prior to study enrollment.
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.
Participants must have a Lansky (≤ 16 years) or (> 16 years) score of at least 50 and, in the opinion of the investigator, a minimum of at least 6 weeks at the time of study enrollment.
Participant must have adequate bone marrow and organ function defined as:
EXCLUSION CRITERIA - OVERALL STUDY - ALL PARTICIPANTS:
(A) INCLUSION CRITERIA - STRATUM A PARTICIPANTS ONLY:
(A) EXCLUSION CRITERIA - STRATUM A PARTICIPANTS ONLY:
(B) INCLUSION CRITERIA - STRATUM B PARTICIPANTS ONLY:
Must meet the following weight and BSA restrictions:
(B) EXCLUSION CRITERIA - STRATUM B PARTICIPANTS ONLY: Participants eligible for this study must NOT meet ANY of the following criteria.
(C) INCLUSION CRITERIA - STRATUM C PARTICIPANTS ONLY:
(C) EXCLUSION CRITERIA - STRATUM C:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Relapsed: the illness came back after treatment had worked. Refractory: it did not respond to treatment, or stopped responding while still on it.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
The amount of disease can be tracked with a defined measurement, so the study can see whether it shrinks or grows. It might be a tumour measured on a scan or, in some blood cancers such as myeloma, a marker measured in blood or urine.
The criteria or the study team say which measurement counts — having no tumour visible on a scan does not by itself rule you out.
Cancer that has spread to the leptomeninges, the thin layers covering the brain and spinal cord, and the fluid between them. It is not the same as brain metastases.
Criteria often treat it separately, and many studies leave it out even where treated brain metastases are allowed.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
CYP3A is a group of enzymes, mainly CYP3A4, in the liver and gut that break down many medicines. Some medicines, supplements and foods (grapefruit, St John’s wort) slow them down or speed them up, which changes how much of a study drug stays in the body.
Studies list them so they can be avoided or switched; bring a list of everything you take, including supplements.
A 0–100 scale of how well someone can carry out everyday activities. 100 is no complaints and no signs of illness; 70 is able to look after yourself but not to work or keep up normal activity; 50 is needing considerable help and frequent medical care.
Studies often ask for 60 or 70 and above. Your doctor gives the score.
The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
Relapsed and refractory
Relapsed: the illness came back after treatment had worked. Refractory: it did not respond to treatment, or stopped responding while still on it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
QT and QTc
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Measurable disease
The amount of disease can be tracked with a defined measurement, so the study can see whether it shrinks or grows. It might be a tumour measured on a scan or, in some blood cancers such as myeloma, a marker measured in blood or urine.
The criteria or the study team say which measurement counts — having no tumour visible on a scan does not by itself rule you out.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Leptomeningeal disease
Cancer that has spread to the leptomeninges, the thin layers covering the brain and spinal cord, and the fluid between them. It is not the same as brain metastases.
Criteria often treat it separately, and many studies leave it out even where treated brain metastases are allowed.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CYP3A (CYP3A4) inhibitors and inducers
CYP3A is a group of enzymes, mainly CYP3A4, in the liver and gut that break down many medicines. Some medicines, supplements and foods (grapefruit, St John’s wort) slow them down or speed them up, which changes how much of a study drug stays in the body.
Studies list them so they can be avoided or switched; bring a list of everything you take, including supplements.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Karnofsky performance status (KPS)
A 0–100 scale of how well someone can carry out everyday activities. 100 is no complaints and no signs of illness; 70 is able to look after yourself but not to work or keep up normal activity; 50 is needing considerable help and frequent medical care.
Studies often ask for 60 or 70 and above. Your doctor gives the score.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Life expectancy
The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Creatinine clearance (CrCl)
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
GFR and eGFR (kidney filtering)
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECG (electrocardiogram)
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
LVEF (left ventricular ejection fraction)
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Stratum A participants with a diagnosis of refractory or recurrent medulloblastoma (Group 3/4) or refractory or recurrent ependymoma. (including: ependymoma, not otherwise specified (NOS), WHO Grade III; ependymoma, RELA fusion positive; anaplastic ependymoma; ependymoma, NOS, WHO grade II). They receive combination treatment with ribociclib and gemcitabine. They may also receive growth therapy support with filgrastim. Stratum A has completed all the necessary accrual
Drug: Gemcitabine · Drug: ribociclib · Biological: filgrastim
Stratum B participants with a diagnosis of one of the following refractory or recurrent CNS diseases: medulloblastoma, \[sonic hedgehog (SHH)- or WNT-activated\];; high grade glioma (including: high grade glioma, (NOS), WHO Grade III or IV; anaplastic astrocytoma, IDH mutant; glioblastoma, IDH-wildtype; glioblastoma, IDH-mutant; diffuse midline glioma, H3K27-mutant; anaplastic oligodendroglioma, IDH mutant and 1p/19q-codeleted; anaplastic pleomorphic xanthoastrocytoma); select CNS embryonal tumors (including: embryonal tumors with multilayered rosettes, C19MC-altered; embryonal tumors with multilayered rosettes, NOS; medulloepithelioma; CNS neuroblastoma; CNS ganglioneuroblastoma; CNS embryonal tumor, NOS; atypical teratoid/rhabdoid tumor; CNS embryonal tumor with rhabdoid features). They receive combination treatment with ribociclib and trametinib. Stratum B has completed all the necessary accrual
Drug: ribociclib · Drug: trametinib
Stratum C participants with refractory or recurrent medulloblastoma (SHH-activated) \>6 months off smoothened inhibitor, presence of 9q loss or PTCH1 mutant, skeletally mature. They received combination treatment with ribociclib and sonidegib. Stratum C is being closed due to low accrual
Drug: ribociclib · Drug: sonidegib
Given intravenously (IV).
Also known as: Gemzar®
Given orally (PO).
Also known as: LEE011, LEE-011, KISQALI®
Given PO.
Also known as: LDE225, LDE-225, ODOMZO®
Given PO.
Also known as: TMT212, TMT-212, MEKINIST(TM)
Given subcutaneously (SQ).
Also known as: G-CSF
Estimate the Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of each doublet by stratum
The MTD is empirically defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level has been determined to be too toxic. The MTD estimate will not be available, if the lowest dose level studied is too toxic or the highest dose level studied is considered safe. In the latter case, the highest studied safe dose will be considered the recommended phase 2 dose (RP2D). The MTD estimation will be limited to evaluable patients and toxicity assessments from course 1 (28 days).
Time frame: 1 month after start of therapy
Pharmacokinetics of combination treatment: Stratum A
Plasma concentration will be provided.
Time frame: Course 1: Days -1, 0, 1 and 15 and 16; Course 2: Day 1
Pharmacokinetics of combination treatment: Stratum B
Plasma concentration will be provided.
Time frame: Course 1: Days 1, 2, 3, 14 and 15
Pharmacokinetics of combination treatment: Stratum C
Plasma concentration will be provided.
Time frame: Course 1: Days -1, 0, 1, 2, 21, 22 and 28; Course 2: Day 1
Response rate by stratum
The response rate, defined as the rate of complete response (CR) or partial response (PR), and long-term stable disease (SD) will be calculated as the percentage of confirmed responders among all response assessable patients. These rates as well as their exact confidence intervals will be provided and will be summarized by each response category (i.e., CR, PR, and SD). Descriptive summaries of response per dose level may also be provided. Subjects without an assessment will be considered non-responders.
Time frame: Up to 1 year after completion of therapy (up to 3 years after start of therapy)
Duration of objective response by stratum
Duration of response defined as the time from the initial documented response (CR or PR) to the first confirmed progressive disease (PD). We will use progression free survival (PFS) for describing duration of SD. Subjects without a documented progression will be censored at the time of their last tumor assessment. Duration of Response will be assessed using the Kaplan-Meier method to calculate the median time as well as the proportion remaining progression free at given time points. The corresponding 95% confidence intervals will be presented.
Time frame: Up to 1 year after completion of therapy (up to 3 years after start of therapy)
Ran from Mar 2018 to primary completion in Sep 2022, 54 months.
Of 240 non-industry phase 1 interventional studies under Glioblastoma, half reached primary completion within 45 months of starting (the median), counting those still running; a quarter within 31 and three quarters within 76. This study's 54 months is above that.
Counting every sponsor, half of 322 studies reached it within 44 months; a quarter within 29 and three quarters within 73.
How these figures are worked out, and which studies are left out of them.
This study is completed, as verified in May 2024. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
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Studies of the drugs tested here: Gemcitabine · Ribociclib · Sonidegib · Trametinib · Filgrastim
St. Jude Children's Research Hospital →