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

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.

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).

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.