Clinical trial NCT01747876: 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
Overall status: TERMINATED
Phase: PHASE1
Conditions: Malignant Rhabdoid Tumors (MRT)
Neuroblastoma
Keywords: LEE011
Phase 1
pediatric
CDK4/6 inhibitor
dose escalation
malignant rhabdoid tumors
MRT
neuroblastoma
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-12-12
Enrollment: 32
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment
timeFrame: cycle 1 = 28 days (from the time of first dose)
Secondary outcomes:
measure: Overall Response Rate
timeFrame: Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
measure: Time to Disease Progression (TTP) Per RECIST 1.1
timeFrame: Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
measure: Duration of Response (DOR)
timeFrame: Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
measure: Pharmacokinetics (PK) Parameter: AUC0-24
timeFrame: 0,1, 2, 4, 8 hours post dose Cycle 1 Day 1 (C1D1) and Cycle 1 Day 15 (C1D15)
measure: Pharmacokinetics (PK) Parameter: Cmax
timeFrame: C1D1, C1D15
measure: Pharmacokinetics (PK) Parameter: Tmax
timeFrame: C1D1, C1D15
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Medical Center Dept of Pediatic Oncology
state: California
city: Atlanta
country: United States
facility: Childrens Healthcare of Atlanta Dept of Oncology
state: Georgia
city: Boston
country: United States
facility: Dana Farber Cancer Institute SC-7
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Dept of Onc
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center Dept of Oncology
state: Ohio
city: Memphis
country: United States
facility: St Jude s Childrens Research Hospital Dept of Oncology
state: Tennessee
city: Perth
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Lyon Cedex
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Augsburg
country: Germany
facility: Novartis Investigative Site
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: