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

NCT01747876 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: CLEE011X21022012-004228-40
• Study Type: interventional
• Target: 32
• Locations: 5 countries
• Sites: 13

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.

Conditions

Malignant Rhabdoid Tumors (MRT); Neuroblastoma

Keywords

LEE011; Phase 1; pediatric; CDK4/6 inhibitor; dose escalation; malignant rhabdoid tumors; MRT; neuroblastoma

Outcome Measures

Primary Outcomes (1)

• 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.

  cycle 1 = 28 days (from the time of first dose)

Secondary Outcomes (6)

• Overall Response Rate

  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

  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)

  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

  0,1, 2, 4, 8 hours post dose Cycle 1 Day 1 (C1D1) and Cycle 1 Day 15 (C1D15)

• Pharmacokinetics (PK) Parameter: Cmax

  C1D1, C1D15

Study Arms (1)

LEE011

EXPERIMENTAL

Drug: LEE011

Interventions

LEE011 DRUG

LEE011 is a small molecule inhibitor of CDK4/6.

LEE011

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (13)

UCSF Medical Center Dept of Pediatic Oncology

San Francisco, California, 94143, United States

Location

Childrens Healthcare of Atlanta Dept of Oncology

Atlanta, Georgia, 30342, United States

Location

Dana Farber Cancer Institute SC-7

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering Dept of Onc

New York, New York, 10017, United States

Location

Cincinnati Children's Hospital Medical Center Dept of Oncology

Cincinnati, Ohio, 45229-3039, United States

Location

St Jude s Childrens Research Hospital Dept of Oncology

Memphis, Tennessee, 38105-2794, United States

Location

Novartis Investigative Site

Perth, Western Australia, 6840, Australia

Location

Novartis Investigative Site

Lyon, 69373, France

Location

Novartis Investigative Site

Paris, 75231, France

Location

Novartis Investigative Site

Villejuif, 94805, France

Location

Novartis Investigative Site

Cologne, North Rhine-Westphalia, 50937, Germany

Location

Novartis Investigative Site

Augsburg, 86156, Germany

Location

Novartis Investigative Site

Sutton, Surrey, SM2 5PT, United Kingdom

Location

MeSH Terms

Conditions

Neuroblastoma

Interventions

ribociclib

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 6, 2012
• First Posted: December 12, 2012
• Study Start: May 28, 2013
• Primary Completion: June 29, 2017
• Study Completion: June 29, 2017
• Last Updated: November 22, 2019
• Results First Posted: February 28, 2019

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1); US (6); FR (3); DE (2); AU (1)