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Study of Safety and Efficacy in Patients With Malignant Rhabdoid Tumors (MRT) and Neuroblastoma

Primary Purpose

Malignant Rhabdoid Tumors (MRT), Neuroblastoma

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
LEE011
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Rhabdoid Tumors (MRT) focused on measuring LEE011, Phase 1, pediatric, CDK4/6 inhibitor, dose escalation, malignant rhabdoid tumors, MRT, neuroblastoma

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.

Sites / Locations

  • UCSF Medical Center Dept of Pediatic Oncology
  • Childrens Healthcare of Atlanta Dept of Oncology
  • Dana Farber Cancer Institute SC-7
  • Memorial Sloan Kettering Dept of Onc
  • Cincinnati Children's Hospital Medical Center Dept of Oncology
  • St Jude s Childrens Research Hospital Dept of Oncology
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

LEE011

Arm Description

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Overall Response Rate
This analysis was not done as there were no responders.
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.
Duration of Response (DOR)
Assess the anti-tumor activity of LEE011 by RECIST 1.1. DOR was not assessed.
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.
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
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.

Full Information

First Posted
December 6, 2012
Last Updated
November 13, 2019
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01747876
Brief Title
Study of Safety and Efficacy in Patients With Malignant Rhabdoid Tumors (MRT) and Neuroblastoma
Official Title
A Phase I, Multi-center, Open-label Study of LEE011 in Patients With Malignant Rhabdoid Tumors and Neuroblastoma
Study Type
Interventional

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Terminated
Why Stopped
Lack of efficacy caused enrollment to be stopped at the end of dose escalation
Study Start Date
May 28, 2013 (Actual)
Primary Completion Date
June 29, 2017 (Actual)
Study Completion Date
June 29, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief 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 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Rhabdoid Tumors (MRT), Neuroblastoma
Keywords
LEE011, Phase 1, pediatric, CDK4/6 inhibitor, dose escalation, malignant rhabdoid tumors, MRT, neuroblastoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
LEE011
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
LEE011
Intervention Description
LEE011 is a small molecule inhibitor of CDK4/6.
Primary Outcome Measure Information:
Title
Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment
Description
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.
Time Frame
cycle 1 = 28 days (from the time of first dose)
Secondary Outcome Measure Information:
Title
Overall Response Rate
Description
This analysis was not done as there were no responders.
Time Frame
Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
Title
Time to Disease Progression (TTP) Per RECIST 1.1
Description
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.
Time Frame
Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
Title
Duration of Response (DOR)
Description
Assess the anti-tumor activity of LEE011 by RECIST 1.1. DOR was not assessed.
Time Frame
Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
Title
Pharmacokinetics (PK) Parameter: AUC0-24
Description
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.
Time Frame
0,1, 2, 4, 8 hours post dose Cycle 1 Day 1 (C1D1) and Cycle 1 Day 15 (C1D15)
Title
Pharmacokinetics (PK) Parameter: Cmax
Description
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
Time Frame
C1D1, C1D15
Title
Pharmacokinetics (PK) Parameter: Tmax
Description
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.
Time Frame
C1D1, C1D15

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Exclusion Criteria: 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
UCSF Medical Center Dept of Pediatic Oncology
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Childrens Healthcare of Atlanta Dept of Oncology
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Dana Farber Cancer Institute SC-7
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Memorial Sloan Kettering Dept of Onc
City
New York
State/Province
New York
ZIP/Postal Code
10017
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center Dept of Oncology
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229-3039
Country
United States
Facility Name
St Jude s Childrens Research Hospital Dept of Oncology
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105-2794
Country
United States
Facility Name
Novartis Investigative Site
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6840
Country
Australia
Facility Name
Novartis Investigative Site
City
Lyon Cedex
ZIP/Postal Code
69373
Country
France
Facility Name
Novartis Investigative Site
City
Paris
ZIP/Postal Code
75231
Country
France
Facility Name
Novartis Investigative Site
City
Villejuif Cedex
ZIP/Postal Code
94805
Country
France
Facility Name
Novartis Investigative Site
City
Koeln
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
50937
Country
Germany
Facility Name
Novartis Investigative Site
City
Augsburg
ZIP/Postal Code
86156
Country
Germany
Facility Name
Novartis Investigative Site
City
Sutton
State/Province
Surrey
ZIP/Postal Code
SM2 5PT
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No

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Study of Safety and Efficacy in Patients With Malignant Rhabdoid Tumors (MRT) and Neuroblastoma

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