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

Phase 1

Terminated

• Conditions: Neuroblastoma; Malignant Rhabdoid Tumors (MRT)
• Interventions: Drug: LEE011

• Registration Number: NCT01747876
• Lead Sponsor: Novartis Pharmaceuticals

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).

Study Timeline

• Study First Submitted: 2012-12-06
• Study First Submitted QC: 2012-12-11
• Study First Posted: 2012-12-12
• Study Start: 2013-05-28
• Primary Completion: 2017-06-29
• Study Completion: 2017-06-29
• Results First Submitted: 2017-12-07
• Results First Submitted QC: 2018-10-25
• Results First Posted: 2019-02-28
• Status Verified: 2019-11
• Last Update Submitted: 2019-11-13
• Last Update Posted: 2019-11-22

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 32

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
LEE011	LEE011	-

Primary Outcome Measures

Name	Time	Method
Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment	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.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics (PK) Parameter: Cmax	C1D1, C1D15	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 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	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.
Pharmacokinetics (PK) Parameter: AUC0-24	0,1, 2, 4, 8 hours post dose Cycle 1 Day 1 (C1D1) and Cycle 1 Day 15 (C1D15)	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.
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	This analysis was not done as there were no responders.
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	Assess the anti-tumor activity of LEE011 by RECIST 1.1. DOR was not assessed.
Pharmacokinetics (PK) Parameter: Tmax	C1D1, C1D15	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.

Trial Locations

Locations (7)

Childrens Healthcare of Atlanta Dept of Oncology; 🇺🇸 Atlanta, Georgia, United States

Dana Farber Cancer Institute SC-7; 🇺🇸 Boston, Massachusetts, United States

Cincinnati Children's Hospital Medical Center Dept of Oncology; 🇺🇸 Cincinnati, Ohio, United States

St Jude s Childrens Research Hospital Dept of Oncology; 🇺🇸 Memphis, Tennessee, United States

Novartis Investigative Site; 🇬🇧 Sutton, Surrey, United Kingdom

Memorial Sloan Kettering Dept of Onc; 🇺🇸 New York, New York, United States

UCSF Medical Center Dept of Pediatic Oncology; 🇺🇸 San Francisco, California, United States