Malignant Rhabdoid Tumors (MRT)Phase 1NCT01747876
Study of Safety and Efficacy in Patients With Malignant Rhabdoid Tumors (MRT) and Neuroblastoma
A Phase 1 study testing LEE011 in people with Malignant Rhabdoid Tumors (MRT) and Neuroblastoma, run by Novartis Pharmaceuticals at 13 sites in 5 countries.
Trial summary
LEE011 is a small molecule inhibitor of CDK4/6. LEE011 has demonstrated in vitro and in vivo activity in both tumor models. The primary purpose of this study was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) in pediatric patients and to delineate a clinical dose to be used… Read more about this study
- Who is it for?
- Ages 1 year to 21 years
- Conditions the study is for
- Malignant Rhabdoid Tumors (MRT), Neuroblastoma
- What is being tested?
- LEE011
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 32 participants
- Where
- 13 sitesin 5 countries
- Study dates
- 28 May 2013to 29 Jun 2017
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Confirmed diagnosis of MRT or, neuroblastoma or in dose escalation part, other tumors with documented evidence of D-cyclin-CDK4/6-INK4a-Rb pathway abnormalities (dose escalation part only),
- Patients with CNS disease should be on stable doses of steroids for at least 7 days prior to first dose of LEE011 with no plans for escalation.
- In expansion part, patients must have at least one measurable disease as defined by RECIST v1.1.
- Patients must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of at least 50.
Who cannot join
- Prior history of QTc prolongation or QTcF > 450 ms on screening ECG.
- Patients with the following laboratory values during screening:
- Serum creatinine > 1.5 x upper limit of normal (ULN) for age
- Total bilirubin >1.5 x ULN for age
- Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) > 3 x ULN for age; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase(SGOT) > 3 x ULN for age except in patients with tumor involvement of the liver who must have AST/SGOT and ALT/SGPT ≤ 5 x ULN for age. For the purpose of this study, the ULN for SGPT/ALT is 45 U/L.
- Patients who are currently receiving treatment with agents that are metabolized predominantly through CYP3A4/5 and have a narrow therapeutic window and/or agents that are known strong inducers or inhibitors CYP3A4/5 are prohibited. In particular, enzyme-inducing antiepileptic drugs (EIAEDs).
- Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for the study.
Trial locations and contacts
13 sites in 5 countries.
13 sites in 5 countries
United States6 sites
Childrens Healthcare of Atlanta Dept of Oncology
Atlanta, Georgia, 30342
Dana Farber Cancer Institute SC-7
Boston, Massachusetts, 02215
Cincinnati Children's Hospital Medical Center Dept of Oncology
Cincinnati, Ohio, 45229-3039
St Jude s Childrens Research Hospital Dept of Oncology
Memphis, Tennessee, 38105-2794
Memorial Sloan Kettering Dept of Onc
New York, New York, 10017
UCSF Medical Center Dept of Pediatic Oncology
San Francisco, California, 94143
France3 sites
Novartis Investigative Site
Lyon, 69373
Novartis Investigative Site
Paris, 75231
Novartis Investigative Site
Villejuif, 94805
Germany2 sites
Novartis Investigative Site
Augsburg, 86156
Novartis Investigative Site
Cologne, North Rhine-Westphalia, 50937
United Kingdom1 site
Novartis Investigative Site
Sutton, Surrey, SM2 5PT
About this study
Official title: A Phase I, Multi-center, Open-label Study of LEE011 in Patients With Malignant Rhabdoid Tumors and Neuroblastoma
LEE011 is a small molecule inhibitor of CDK4/6. LEE011 has demonstrated in vitro and in vivo activity in both tumor models. The primary purpose of this study was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) in pediatric patients and to delineate a clinical dose to be used in future studies. This study was also to have assessed the safety, tolerability, PK and preliminary evidence of antitumor activity of LEE011 in patients with MRT or neuroblastoma.
Read the detailed description
Due to lack of efficacy, enrollment in the study was stopped at the end of dose escalation (sites were notified of the early enrollment halt on 7-Aug-2014) and the dose-expansion part was not conducted. Due to halted enrollment and/or lack of complete responses (CR) and partial responses (PR), efficacy analysis was only performed in terms of TTP for the patients treated during the dose-escalation part at the maximum tolerated dose (MTD) and recommended dose expansion (RDE).
- Conditions
- Malignant Rhabdoid Tumors (MRT), Neuroblastoma
- Being tested
- LEE011
- Keywords
- LEE011, Phase 1, pediatric, CDK4/6 inhibitor, dose escalation, malignant rhabdoid tumors, MRT, neuroblastoma
- Medical subject headings
- Neuroblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LEE011Drug
LEE011 is a small molecule inhibitor of CDK4/6.
| Study group | Role | What they receive |
|---|---|---|
| LEE011 | Experimental | Not described Receives: Drug: LEE011 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment
A DLT was defined as an AE or clinically significant abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first 28 days of treatment with LEE011 and met any of the predefined criteria. For the purpose of dose-escalation decisions, DLTs were considered and included in the Bayesian Logistic Regression Model (BLRM). Patients who did not experience DLT during the first cycle were considered to have had sufficient safety evaluations if they were observed for ≥ 28 days following the first dose and were considered to have had enough safety data to conclude that a DLT did not occur. Patients who did not meet these minimum safety evaluation requirements were regarded as ineligible for the DDS. A patient with multiple DLTs within a primary system organ class is counted only once in the total row.
Measured: cycle 1 = 28 days (from the time of first dose)
Secondary outcomes (6)
Overall Response Rate
This analysis was not done as there were no responders.
Measured: Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
Time to Disease Progression (TTP) Per RECIST 1.1
TTP was assessed per Investigator, for the malignant rhabdoid tumor (MRT) \& neuroblastoma patients for the pooled maximum tolerated dose (MTD) \& recommended dose for expansion (RDE) according to RECIST 1.1 criteria using Kaplan-Meier method. Time to progression (TTP) is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to underlying cancer. If a patient had not had an event, time to progression was censored at the date of last adequate tumor assessment. At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Measured: Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
Duration of Response (DOR)
Assess the anti-tumor activity of LEE011 by RECIST 1.1. DOR was not assessed.
Measured: Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
Pharmacokinetics (PK) Parameter: AUC0-24
The AUC calculated to the end of a dosing interval (tau) following single dose or at steady-state (amount x time x volume-1). PK parameters were estimated from individual plasma concentration-time profiles using noncompartmental methods in Phoenix WinNonlin.
Measured: 0,1, 2, 4, 8 hours post dose Cycle 1 Day 1 (C1D1) and Cycle 1 Day 15 (C1D15)
Pharmacokinetics (PK) Parameter: Cmax
Cmax is the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration or at steady-state (mass x volume-1). PK parameters were estimated from individual plasma concentration-time profiles using noncompartmental methods in Phoenix WinNonlin
Measured: C1D1, C1D15
Pharmacokinetics (PK) Parameter: Tmax
Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration or at steady-state (time). PK parameters were estimated from individual plasma concentration-time profiles using noncompartmental methods in Phoenix WinNonlin.
Measured: C1D1, C1D15
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Dec 2012 (estimated)
- Study start28 May 2013
- Primary completion29 Jun 2017
- Study completion29 Jun 2017
Why it stopped: Lack of efficacy caused enrollment to be stopped at the end of dose escalation
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Malignant Rhabdoid Tumors (MRT)Studies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 32 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01747876
- Sponsor's protocol ID
- CLEE011X2102
- Other IDs
- 2012-004228-40
- Status last verified
- Nov 2019
- First submitted
- 6 Dec 2012
- Last updated
- 22 Nov 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 Nov 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I, Multi-center, Open-label Study of LEE011 in Patients With Malignant Rhabdoid Tumors and Neuroblastoma
- ClinicalTrials.gov ID
- NCT01747876
- Acronym / sponsor ID
- CLEE011X2102
- Conditions
- Malignant Rhabdoid Tumors (MRT), Neuroblastoma
- Keywords
- LEE011, Phase 1, pediatric, CDK4/6 inhibitor, dose escalation, malignant rhabdoid tumors, MRT, neuroblastoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Lack of efficacy caused enrollment to be stopped at the end of dose escalation
- Enrolment
- 32 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 28 May 2013 (actual)
- Primary completion
- 29 Jun 2017 (actual)
- Study completion
- 29 Jun 2017 (actual)
- First posted
- 12 Dec 2012 (estimated)
- Results
- Posted 28 Feb 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
LEE011 is a small molecule inhibitor of CDK4/6. LEE011 has demonstrated in vitro and in vivo activity in both tumor models. The primary purpose of this study was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) in pediatric patients and to delineate a clinical dose to be used in future studies. This study was also to have assessed the safety, tolerability, PK and preliminary evidence of antitumor activity of LEE011 in patients with MRT or neuroblastoma.
Detailed description
Due to lack of efficacy, enrollment in the study was stopped at the end of dose escalation (sites were notified of the early enrollment halt on 7-Aug-2014) and the dose-expansion part was not conducted. Due to halted enrollment and/or lack of complete responses (CR) and partial responses (PR), efficacy analysis was only performed in terms of TTP for the patients treated during the dose-escalation part at the maximum tolerated dose (MTD) and recommended dose expansion (RDE).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| LEE011 | Experimental | Drug: LEE011 |
Who may qualify
- Ages
- 1 year to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (4 listed)
- Confirmed diagnosis of MRT or, neuroblastoma or in dose escalation part, other tumors with documented evidence of D-cyclin-CDK4/6-INK4a-Rb pathway abnormalities (dose escalation part only),
- Patients with CNS disease should be on stable doses of steroids for at least 7 days prior to first dose of LEE011 with no plans for escalation.
- In expansion part, patients must have at least one measurable disease as defined by RECIST v1.1.
- Patients must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of at least 50.
Key exclusion criteria (7 listed)
- Prior history of QTc prolongation or QTcF > 450 ms on screening ECG.
- Patients with the following laboratory values during screening:
- Patients who are currently receiving treatment with agents that are metabolized predominantly through CYP3A4/5 and have a narrow therapeutic window and/or agents that are known strong inducers or inhibitors CYP3A4/5 are prohibited. In particular, enzyme-inducing antiepileptic drugs (EIAEDs).
- Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LEE011LEE011 is a small molecule inhibitor of CDK4/6. | Drug | LEE011 |
Primary outcome
Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment
Time frame: cycle 1 = 28 days (from the time of first dose)
A DLT was defined as an AE or clinically significant abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first 28 days of treatment with LEE011 and met any of the predefined criteria. For the purpose of dose-escalation decisions, DLTs were considered and included in the Bayesian Logistic Regression Model (BLRM). Patients who did not experience DLT during the first cycle were considered to have had sufficient safety evaluations if they were observed for ≥ 28 days following the first dose and were considered to have had enough safety data to conclude that a DLT did not occur. Patients who did not meet these minimum safety evaluation requirements were regarded as ineligible for the DDS. A patient with multiple DLTs within a primary system organ class is counted only once in the total row.
6 secondary outcomes
Overall Response Rate
Time frame: Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
Time to Disease Progression (TTP) Per RECIST 1.1
Time frame: Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
Duration of Response (DOR)
Time frame: Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
Pharmacokinetics (PK) Parameter: AUC0-24
Time frame: 0,1, 2, 4, 8 hours post dose Cycle 1 Day 1 (C1D1) and Cycle 1 Day 15 (C1D15)
Pharmacokinetics (PK) Parameter: Cmax
Time frame: C1D1, C1D15
Pharmacokinetics (PK) Parameter: Tmax
Time frame: C1D1, C1D15
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Nov 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
13 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing LEE011 in people with Malignant Rhabdoid Tumors (MRT) and Neuroblastoma, run by Novartis Pharmaceuticals at 13 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 22 Nov 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in United States, France, Germany, Australia, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Feb 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment (time frame: cycle 1 = 28 days (from the time of first dose)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Nov 2019.