Trial Outcomes & Findings for Study of Safety and Efficacy in Patients With Malignant Rhabdoid Tumors (MRT) and Neuroblastoma (NCT NCT01747876)

Last Updated: 2019-11-22

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

32 participants

Primary outcome timeframe

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

Results posted on

2019-11-22

Participant Flow

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.

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).

Participant milestones

Participant milestones
Measure	LEE011 280 mg/m2 - Dose Escalation Only Patients who took 280 mg/m2 of LEE011	LEE011 350 mg/m2 - Dose Escalation Only Patients who took 350 mg/m2 of LEE011. The dose escalation part of the study	LEE011 470 mg/m2 - Dose Escalation Only Patients who took 470 mg/m2 of LEE011
Overall Study STARTED	5	15	12
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	5	15	12

Reasons for withdrawal

Reasons for withdrawal
Measure	LEE011 280 mg/m2 - Dose Escalation Only Patients who took 280 mg/m2 of LEE011	LEE011 350 mg/m2 - Dose Escalation Only Patients who took 350 mg/m2 of LEE011. The dose escalation part of the study	LEE011 470 mg/m2 - Dose Escalation Only Patients who took 470 mg/m2 of LEE011
Overall Study Adverse Event	1	0	2
Overall Study Withdrawal by Subject	0	1	1
Overall Study Disease progression	4	13	8
Overall Study Trtment duration compl. as per protocol	0	1	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LEE011 280 mg/m2 - Dose Escalation Only n=5 Participants Patients who took 280 mg/m2 of LEE011	LEE011 350 mg/m2 - Dose Escalation Only n=15 Participants Patients who took 350 mg/m2 of LEE011. The dose escalation part of the study	LEE011 470 mg/m2 - Dose Escalation Only n=12 Participants Patients who took 470 mg/m2 of LEE011	Total n=32 Participants Total of all reporting groups
Age, Customized 1 to <2	2 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Age, Customized 2 to <5	2 Participants n=5 Participants	7 Participants n=7 Participants	4 Participants n=5 Participants	13 Participants n=4 Participants
Age, Customized 6 to <12	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	6 Participants n=4 Participants
Age, Customized 12 to <18	1 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	7 Participants n=4 Participants
Age, Customized >= 18	0 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	3 Participants n=4 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	6 Participants n=7 Participants	4 Participants n=5 Participants	11 Participants n=4 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	9 Participants n=7 Participants	8 Participants n=5 Participants	21 Participants n=4 Participants
Race/Ethnicity, Customized Caucasian	2 Participants n=5 Participants	10 Participants n=7 Participants	9 Participants n=5 Participants	21 Participants n=4 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Other	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants
Race/Ethnicity, Customized Not Available	2 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	6 Participants n=4 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	LEE011 280 mg/m2 - Dose Escalation Only n=5 Participants Patients who took 280 mg/m2 of LEE011	LEE011 350 mg/m2 - Dose Escalation Only n=15 Participants Patients who took 350 mg/m2 of LEE011. The dose escalation part of the study	LEE011 470 mg/m2 - Dose Escalation Only n=10 Participants Patients who took 470 mg/m2 of LEE011
Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment Gen. disorders & admin. site conditions (fatigue)	1 Participants	0 Participants	0 Participants
Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment Any primary system organ class total	1 Participants	0 Participants	2 Participants
Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment Blood & lymphatic sys. disorders(Thrombocytopenia)	0 Participants	0 Participants	1 Participants
Incidence Rate of Dose Limiting Toxicities (DLTs) by Primary System Organ Class, Preferred Term and Treatment Investigations (Platelet count decreased)	0 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: 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.

This analysis was not done as there were no responders.

Outcome measures

Outcome measures
Measure	LEE011 280 mg/m2 - Dose Escalation Only n=5 Participants Patients who took 280 mg/m2 of LEE011	LEE011 350 mg/m2 - Dose Escalation Only n=15 Participants Patients who took 350 mg/m2 of LEE011. The dose escalation part of the study	LEE011 470 mg/m2 - Dose Escalation Only n=12 Participants Patients who took 470 mg/m2 of LEE011
Overall Response Rate	NA months This analysis was not done as there were no responders.	NA months This analysis was not done as there were no responders.	NA months This analysis was not done as there were no responders.

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	LEE011 280 mg/m2 - Dose Escalation Only n=11 Participants Patients who took 280 mg/m2 of LEE011	LEE011 350 mg/m2 - Dose Escalation Only n=14 Participants Patients who took 350 mg/m2 of LEE011. The dose escalation part of the study	LEE011 470 mg/m2 - Dose Escalation Only Patients who took 470 mg/m2 of LEE011
Time to Disease Progression (TTP) Per RECIST 1.1	1.8 months Interval 1.7 to 2.0	1.8 months Interval 1.7 to 4.4	—

SECONDARY outcome

Timeframe: 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.

Assess the anti-tumor activity of LEE011 by RECIST 1.1. DOR was not assessed.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	LEE011 280 mg/m2 - Dose Escalation Only n=5 Participants Patients who took 280 mg/m2 of LEE011	LEE011 350 mg/m2 - Dose Escalation Only n=12 Participants Patients who took 350 mg/m2 of LEE011. The dose escalation part of the study	LEE011 470 mg/m2 - Dose Escalation Only n=7 Participants Patients who took 470 mg/m2 of LEE011
Pharmacokinetics (PK) Parameter: AUC0-24 C1D1	9250 h*ng/ml Interval 4580.0 to 22000.0	10000 h*ng/ml Interval 5320.0 to 43600.0	17600 h*ng/ml Interval 8010.0 to 28500.0
Pharmacokinetics (PK) Parameter: AUC0-24 C1D15	13800 h*ng/ml Interval 8910.0 to 60100.0	24500 h*ng/ml Interval 15100.0 to 60100.0	29100 h*ng/ml Interval 13300.0 to 50500.0

SECONDARY outcome

Timeframe: C1D1, C1D15

Population: The pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable drug concentration data.

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

Outcome measures

Outcome measures
Measure	LEE011 280 mg/m2 - Dose Escalation Only n=5 Participants Patients who took 280 mg/m2 of LEE011	LEE011 350 mg/m2 - Dose Escalation Only n=12 Participants Patients who took 350 mg/m2 of LEE011. The dose escalation part of the study	LEE011 470 mg/m2 - Dose Escalation Only n=10 Participants Patients who took 470 mg/m2 of LEE011
Pharmacokinetics (PK) Parameter: Cmax C1D1	937 ng/ml Interval 542.0 to 1910.0	1130 ng/ml Interval 514.0 to 4140.0	1960 ng/ml Interval 796.0 to 4360.0
Pharmacokinetics (PK) Parameter: Cmax C1D15	1110 ng/ml Interval 860.0 to 5210.0	2010 ng/ml Interval 633.0 to 4270.0	2500 ng/ml Interval 562.0 to 5050.0

SECONDARY outcome

Timeframe: C1D1, C1D15

Population: The pharmacokinetic analysis set (PAS) consisted of all patients who had at least one blood sample providing evaluable drug concentration data.

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.

Outcome measures

Outcome measures
Measure	LEE011 280 mg/m2 - Dose Escalation Only n=5 Participants Patients who took 280 mg/m2 of LEE011	LEE011 350 mg/m2 - Dose Escalation Only n=12 Participants Patients who took 350 mg/m2 of LEE011. The dose escalation part of the study	LEE011 470 mg/m2 - Dose Escalation Only n=10 Participants Patients who took 470 mg/m2 of LEE011
Pharmacokinetics (PK) Parameter: Tmax C1D1	2.03 hour Interval 1.1 to 4.08	2.02 hour Interval 1.0 to 4.05	4 hour Interval 2.0 to 4.07
Pharmacokinetics (PK) Parameter: Tmax C1D15	2.08 hour Interval 1.13 to 3.83	2.13 hour Interval 1.08 to 23.8	3.92 hour Interval 1.98 to 23.6

Adverse Events

LEE011 280 mg/m2 - Dose Escalation Only

Serious events: 3 serious events

Other events: 5 other events

Deaths: 2 deaths

LEE011 350 mg/m2 - Dose Escalation Only

Serious events: 7 serious events

Other events: 15 other events

Deaths: 2 deaths

LEE011 470 mg/m2 - Dose Escalation Only

Serious events: 4 serious events

Other events: 12 other events

Deaths: 1 deaths

All Patients

Serious events: 14 serious events

Other events: 32 other events

Deaths: 5 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER

Measure	LEE011 280 mg/m2 - Dose Escalation Only n=5 participants at risk Patients who took 280 mg/m2 of LEE011	LEE011 350 mg/m2 - Dose Escalation Only n=15 participants at risk Patients who took 350 mg/m2 of LEE011. The dose escalation part of the study	LEE011 470 mg/m2 - Dose Escalation Only n=12 participants at risk Patients who took 470 mg/m2 of LEE011	All Patients n=32 participants at risk All patients who took either 280 mg/m2 or 350 mg/m2 or 470 mg/m2 of LEE011
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Eye disorders Orbital oedema	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	8.3% 1/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Gastrointestinal disorders Abdominal pain	20.0% 1/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
General disorders Face oedema	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	8.3% 1/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
General disorders Pain	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
General disorders Pyrexia	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	13.3% 2/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.2% 2/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Infections and infestations Device related infection	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Infections and infestations Influenza	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	8.3% 1/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Infections and infestations Pneumococcal bacteraemia	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Infections and infestations Pneumococcal infection	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	8.3% 1/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Infections and infestations Pneumonia	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Investigations Lymphocyte count decreased	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Metabolism and nutrition disorders Decreased appetite	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	8.3% 1/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Metabolism and nutrition disorders Dehydration	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Metabolism and nutrition disorders Hypercalcaemia	20.0% 1/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Metabolism and nutrition disorders Polydipsia	20.0% 1/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Central nervous system neuroblastoma	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Nervous system disorders Brain oedema	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	8.3% 1/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Nervous system disorders Depressed level of consciousness	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	8.3% 1/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Nervous system disorders Extrapyramidal disorder	20.0% 1/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Nervous system disorders Febrile convulsion	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Nervous system disorders Headache	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	16.7% 2/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.2% 2/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Nervous system disorders Hydrocephalus	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	8.3% 1/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Nervous system disorders Intracranial pressure increased	20.0% 1/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Nervous system disorders Seizure	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Psychiatric disorders Irritability	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	8.3% 1/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Renal and urinary disorders Polyuria	20.0% 1/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Respiratory, thoracic and mediastinal disorders Apnoea	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	8.3% 1/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/5 • From date of first administration of study treatment to 30 days after date of last actual administration of study	6.7% 1/15 • From date of first administration of study treatment to 30 days after date of last actual administration of study	0.00% 0/12 • From date of first administration of study treatment to 30 days after date of last actual administration of study	3.1% 1/32 • From date of first administration of study treatment to 30 days after date of last actual administration of study