Malignant Rhabdoid Tumors (MRT), Neuroblastoma
Conditions
Keywords
LEE011, Phase 1, pediatric, CDK4/6 inhibitor, dose escalation, malignant rhabdoid tumors, MRT, neuroblastoma
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).
Interventions
DRUGLEE011
LEE011 is a small molecule inhibitor of CDK4/6.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 21 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
Countries
Australia, France, Germany, United Kingdom, United States
Participant flow
Recruitment details
Approximately 64 patients were to be treated during the entire study; however, 32 patients were enrolled and treated at the time of the enrollment halt.
Pre-assignment details
The escalation part of the study explored the 3 doses 280, 350 & 470 mg/m2) in successive cohorts. The dose expansion phase of the study was not conducted (due to enrollment halt).
Participants by arm
| Arm | Count |
|---|---|
| LEE011 280 mg/m2 - Dose Escalation Only Patients who took 280 mg/m2 of LEE011 | 5 |
| LEE011 350 mg/m2 - Dose Escalation Only Patients who took 350 mg/m2 of LEE011. The dose escalation part of the study | 15 |
| LEE011 470 mg/m2 - Dose Escalation Only Patients who took 470 mg/m2 of LEE011 | 12 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 2 |
| Overall Study | Disease progression | 4 | 13 | 8 |
| Overall Study | Trtment duration compl. as per protocol | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | LEE011 470 mg/m2 - Dose Escalation Only | LEE011 350 mg/m2 - Dose Escalation Only | LEE011 280 mg/m2 - Dose Escalation Only |
|---|---|---|---|---|
| Age, Customized 12 to <18 | 7 Participants | 2 Participants | 4 Participants | 1 Participants |
| Age, Customized >= 18 | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Age, Customized 1 to <2 | 3 Participants | 1 Participants | 0 Participants | 2 Participants |
| Age, Customized 2 to <5 | 13 Participants | 4 Participants | 7 Participants | 2 Participants |
| Age, Customized 6 to <12 | 6 Participants | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 21 Participants | 9 Participants | 10 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Available | 6 Participants | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 2 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Female | 11 Participants | 4 Participants | 6 Participants | 1 Participants |
| Sex: Female, Male Male | 21 Participants | 8 Participants | 9 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 5 | 2 / 15 | 1 / 12 | 5 / 32 |
| other Total, other adverse events | 5 / 5 | 15 / 15 | 12 / 12 | 32 / 32 |
| serious Total, serious adverse events | 3 / 5 | 7 / 15 | 4 / 12 | 14 / 32 |
Outcome results
Primary
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.
Time frame: cycle 1 = 28 days (from the time of first dose)
Population: Dose-determining analysis set consisted of all pts from safety set who either met the following minimum exposure criterion \& had scheduled safety evaluations, or experienced a DLT. A patient was considered to have met the minimum exposure criterion if he/she had received at least 16 of 21 planned daily doses of LEE011 in first 28 days of dosing.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LEE011 280 mg/m2 - Dose Escalation Only | Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment | Any primary system organ class total | 1 Participants |
| LEE011 280 mg/m2 - Dose Escalation Only | Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment | Blood & lymphatic sys. disorders(Thrombocytopenia) | 0 Participants |
| LEE011 280 mg/m2 - Dose Escalation Only | Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment | Gen. disorders & admin. site conditions (fatigue) | 1 Participants |
| LEE011 280 mg/m2 - Dose Escalation Only | Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment | Investigations (Platelet count decreased) | 0 Participants |
| LEE011 350 mg/m2 - Dose Escalation Only | Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment | Investigations (Platelet count decreased) | 0 Participants |
| LEE011 350 mg/m2 - Dose Escalation Only | Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment | Any primary system organ class total | 0 Participants |
| LEE011 350 mg/m2 - Dose Escalation Only | Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment | Gen. disorders & admin. site conditions (fatigue) | 0 Participants |
| LEE011 350 mg/m2 - Dose Escalation Only | Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment | Blood & lymphatic sys. disorders(Thrombocytopenia) | 0 Participants |
| LEE011 470 mg/m2 - Dose Escalation Only | Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment | Investigations (Platelet count decreased) | 1 Participants |
| LEE011 470 mg/m2 - Dose Escalation Only | Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment | Blood & lymphatic sys. disorders(Thrombocytopenia) | 1 Participants |
| LEE011 470 mg/m2 - Dose Escalation Only | Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment | Gen. disorders & admin. site conditions (fatigue) | 0 Participants |
| LEE011 470 mg/m2 - Dose Escalation Only | Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment | Any primary system organ class total | 2 Participants |
Secondary
Duration of Response (DOR)
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
Population: Full analysis set included all patients who received at least 1 dose of LEE011. Due to halted enrollment and/or lack of complete responses (CR) \& partial responses (PR), efficacy analysis was only performed in terms of DOR for the patients treated during the dose-escalation part at the MTD and RDE. Therefore, Duration of response was not assessed.
Secondary
Overall Response Rate
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
Population: Full analysis set (FAS) included all patients who received at least one dose of LEE011. This analysis was not done as there were no responders.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LEE011 280 mg/m2 - Dose Escalation Only | Overall Response Rate | NA months |
| LEE011 350 mg/m2 - Dose Escalation Only | Overall Response Rate | NA months |
| LEE011 470 mg/m2 - Dose Escalation Only | Overall Response Rate | NA months |
Secondary
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.
Time frame: 0,1, 2, 4, 8 hours post dose Cycle 1 Day 1 (C1D1) and Cycle 1 Day 15 (C1D15)
Population: The pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable drug concentration data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LEE011 280 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: AUC0-24 | C1D1 | 9250 h*ng/ml |
| LEE011 280 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: AUC0-24 | C1D15 | 13800 h*ng/ml |
| LEE011 350 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: AUC0-24 | C1D1 | 10000 h*ng/ml |
| LEE011 350 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: AUC0-24 | C1D15 | 24500 h*ng/ml |
| LEE011 470 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: AUC0-24 | C1D1 | 17600 h*ng/ml |
| LEE011 470 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: AUC0-24 | C1D15 | 29100 h*ng/ml |
Secondary
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
Time frame: C1D1, C1D15
Population: The pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable drug concentration data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LEE011 280 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: Cmax | C1D1 | 937 ng/ml |
| LEE011 280 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: Cmax | C1D15 | 1110 ng/ml |
| LEE011 350 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: Cmax | C1D1 | 1130 ng/ml |
| LEE011 350 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: Cmax | C1D15 | 2010 ng/ml |
| LEE011 470 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: Cmax | C1D1 | 1960 ng/ml |
| LEE011 470 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: Cmax | C1D15 | 2500 ng/ml |
Secondary
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.
Time frame: C1D1, C1D15
Population: The pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable drug concentration data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LEE011 280 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: Tmax | C1D1 | 2.03 hour |
| LEE011 280 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: Tmax | C1D15 | 2.08 hour |
| LEE011 350 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: Tmax | C1D1 | 2.02 hour |
| LEE011 350 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: Tmax | C1D15 | 2.13 hour |
| LEE011 470 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: Tmax | C1D1 | 4 hour |
| LEE011 470 mg/m2 - Dose Escalation Only | Pharmacokinetics (PK) Parameter: Tmax | C1D15 | 3.92 hour |
Secondary
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.
Time frame: Every 2 cycles (cycle = 28 days) up to end of treatment, the maximum time a patient was on study was 1311 days
Population: Full analysis set (FAS) included all patients who received at least one dose of LEE011.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LEE011 280 mg/m2 - Dose Escalation Only | Time to Disease Progression (TTP) Per RECIST 1.1 | 1.8 months |
| LEE011 350 mg/m2 - Dose Escalation Only | Time to Disease Progression (TTP) Per RECIST 1.1 | 1.8 months |