Trial Outcomes & Findings for A Study of the Safety and Preliminary Efficacy of Oral Midostaurin (PKC412) in Relapsed or Refractory Pediatric Leukemia (NCT NCT00866281)

Last Updated: 2015-12-22

Results Overview

MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced dose limiting toxicity (DLT), based on a Bayesian logistic regression model (BLRM) employing the escalation with overdose control (EWOC) principle. A DLT was defined as a grade 3 or 4 non-hematological adverse event (AE) or abnormal laboratory value related to study drug. Mean and the 95% posterior probability estimates of having a DLT by age strata and dose is presented. Estimation of MTD and/or recommended dose for expansion (RDE) at the dose-escalation phase of the study was based upon the estimation of the probability of DLT for participants in the dose-determining set (DDS).

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

22 participants

Primary outcome timeframe

Baseline, End of dose escalation phase (6 months)

Results posted on

2015-12-22

Participant Flow

The study was conducted at 8 centers in 5 countries.

A total of 22 participants were enrolled in the study.

Participant milestones

Participant milestones
Measure	Cohort 1: Midostaurin (30 Milligrams/Meters^2) Participants received bodyweight and body surface area (BSA) stratified dose of midostaurin 30 mg/m\^2 twice daily (bid) through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.	Cohort 2: Midostaurin (60 mg/m^2) Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m\^2 bid through oral route. The total daily dose in 60 mg/m\^2 bid cohort was 120 mg/m\^2.
Overall Study STARTED	7	15
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	7	15

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1: Midostaurin (30 Milligrams/Meters^2) Participants received bodyweight and body surface area (BSA) stratified dose of midostaurin 30 mg/m\^2 twice daily (bid) through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.	Cohort 2: Midostaurin (60 mg/m^2) Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m\^2 bid through oral route. The total daily dose in 60 mg/m\^2 bid cohort was 120 mg/m\^2.
Overall Study Adverse Event	1	0
Overall Study Withdrawal by participants	3	0
Overall Study Disease progression	3	11
Overall Study New cancer therapy	0	4

Baseline Characteristics

A Study of the Safety and Preliminary Efficacy of Oral Midostaurin (PKC412) in Relapsed or Refractory Pediatric Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1: Midostaurin (30 Milligrams/Meters^2) n=7 Participants Participants received body-weight and BSA stratified dose of midostaurin 30 mg/m\^2 bid through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.	Cohort 2: Midostaurin (60 mg/m^2) n=15 Participants Participants received body-weight and BSA stratified dose of midostaurin 60 mg/m\^2 bid through oral route. The total daily dose in 60 mg/m\^2 bid cohort was 120 mg/m\^2.	Total n=22 Participants Total of all reporting groups
Age, Continuous	9.65 years STANDARD_DEVIATION 7.479 • n=5 Participants	6.50 years STANDARD_DEVIATION 6.903 • n=7 Participants	7.50 years STANDARD_DEVIATION 7.070 • n=5 Participants
Age, Customized Infants and toddlers (28 days-23 months)	2 participants n=5 Participants	9 participants n=7 Participants	11 participants n=5 Participants
Age, Customized Children (2--11 years)	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Age, Customized Adolescents (12--17 years)	4 participants n=5 Participants	5 participants n=7 Participants	9 participants n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	10 Participants n=7 Participants	15 Participants n=5 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	5 Participants n=7 Participants	7 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, End of dose escalation phase (6 months)

Population: The analysis was performed in dose determining set (DDS) population. Here, 'n' signifies the number of evaluable participants for this measure.

Outcome measures

Outcome measures
Measure	Cohort 1: Midostaurin (30 Milligrams/Meters^2) n=6 Participants Participants received bodyweight and BSA stratified dose of midostaurin 30 mg/m\^2 bid through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.	Cohort 2: Midostaurin (60 mg/m^2) n=11 Participants Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m\^2 bid through oral route. The total daily dose in 60 mg/m\^2 bid cohort was 120 mg/m\^2.
Maximum Tolerated Dose (MTD) of Midostaurin- Posterior Probability of DLT Younger stratum (≥ 3months -≤ 2 years): (n=2, 5)	0.03 probability estimates Interval 0.0 to 0.16	0.10 probability estimates Interval 0.01 to 0.33
Maximum Tolerated Dose (MTD) of Midostaurin- Posterior Probability of DLT Older stratum (>2 years- <18years): (n=4,6)	0.03 probability estimates Interval 0.0 to 0.13	0.08 probability estimates Interval 0.01 to 0.26

SECONDARY outcome

Timeframe: Baseline, Day 15 (Day 1 of Cycle 2), Day 22 (Day 8 of Cycle 2), Day 29(Day 1 of Cycle 9), End of treatment (up to 24 months after last dose or until death whichever occurred first)

Population: The analysis was performed in full analysis set (FAS) population, defined as all participants to whom study treatment was assigned.

The best overall clinical response was determined as per the clinical assessment done by the investigator. Responders were defined as all participants with a best clinical response of leukemia free state, morphological complete remission, incomplete morphological complete remission, partial remission, bone marrow blast response, bone marrow minor blast response, peripheral blood blast response, minor peripheral blood blast response. Participants with stable disease, progressive disease and with missing tumour assessment or who discontinued the study or who died before having their first assessment were considered as non-responders. Stable disease was defined as failure to achieve any of the above response. Progressive disease was defined as doubling of the bone marrow blast percentage from baseline in participants with \<40% bone marrow blasts at baseline, or a 50% increase in bone marrow blast percentage from baseline in participants with \>40% bone marrow blasts at baseline,

Outcome measures

Outcome measures
Measure	Cohort 1: Midostaurin (30 Milligrams/Meters^2) n=9 Participants Participants received bodyweight and BSA stratified dose of midostaurin 30 mg/m\^2 bid through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.	Cohort 2: Midostaurin (60 mg/m^2) n=13 Participants Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m\^2 bid through oral route. The total daily dose in 60 mg/m\^2 bid cohort was 120 mg/m\^2.
Percentage of Participants With Best Overall Response by Indication Leukemia free state	0 Percentage of Participants	0 Percentage of Participants
Percentage of Participants With Best Overall Response by Indication Morphological complete remission	0 Percentage of Participants	0 Percentage of Participants
Percentage of Participants With Best Overall Response by Indication Incomplete morphological complete remission	11.1 Percentage of Participants	0 Percentage of Participants
Percentage of Participants With Best Overall Response by Indication Partial remission	0 Percentage of Participants	0 Percentage of Participants
Percentage of Participants With Best Overall Response by Indication Bone marrow blast response	22.2 Percentage of Participants	0 Percentage of Participants
Percentage of Participants With Best Overall Response by Indication Bone marrow minor blast response	0 Percentage of Participants	0 Percentage of Participants
Percentage of Participants With Best Overall Response by Indication Peripheral blood blast response	11.1 Percentage of Participants	23.1 Percentage of Participants
Percentage of Participants With Best Overall Response by Indication Minor peripheral blood blast response	11.1 Percentage of Participants	0 Percentage of Participants
Percentage of Participants With Best Overall Response by Indication Stable disease	44.4 Percentage of Participants	7.7 Percentage of Participants
Percentage of Participants With Best Overall Response by Indication Progressive disease	0 Percentage of Participants	61.5 Percentage of Participants
Percentage of Participants With Best Overall Response by Indication Not Done	0 Percentage of Participants	7.7 Percentage of Participants
Percentage of Participants With Best Overall Response by Indication Participants with response	55.6 Percentage of Participants	23.1 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first)

Population: The analysis was performed in FAS population. Here, "Number of participants analysed" signifies number of responders at specified time points for each arm, respectively.

Time to response was defined as the time from the date of start of midostaurin treatment to the date of first response. The best overall clinical response was determined as per the clinical assessment done by the investigator. Responders were defined as all participants with a best clinical response of leukemia free state, morphological complete remission, incomplete morphological complete remission, partial remission, bone marrow blast response, bone marrow minor blast response, peripheral blood blast response, minor peripheral blood blast response. Time to response was calculated by using the formula = (date of first response -date of start of midostaurin) +1 day.

Outcome measures

Outcome measures
Measure	Cohort 1: Midostaurin (30 Milligrams/Meters^2) n=5 Participants Participants received bodyweight and BSA stratified dose of midostaurin 30 mg/m\^2 bid through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.	Cohort 2: Midostaurin (60 mg/m^2) n=3 Participants Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m\^2 bid through oral route. The total daily dose in 60 mg/m\^2 bid cohort was 120 mg/m\^2.
Time to Response With Midostaurin	14.0 Days Interval 8.0 to 22.0	8.0 Days Interval 3.0 to 8.0

SECONDARY outcome

Timeframe: Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first)

Population: The analysis was performed in FAS population.

Overall survival (OS) was defined as the time from start of treatment to date of death due to any cause. The percentage (%) event-free probability estimates were obtained from the Kaplan-Meier survival estimates.

Outcome measures

Outcome measures
Measure	Cohort 1: Midostaurin (30 Milligrams/Meters^2) n=9 Participants Participants received bodyweight and BSA stratified dose of midostaurin 30 mg/m\^2 bid through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.	Cohort 2: Midostaurin (60 mg/m^2) n=13 Participants Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m\^2 bid through oral route. The total daily dose in 60 mg/m\^2 bid cohort was 120 mg/m\^2.
Overall Survival With Midostaurin	3.68 Months Interval 2.727 to 8.312	1.35 Months Interval 0.953 to 2.924

SECONDARY outcome

Timeframe: Day 1, Day 5, Day 7, Day 15 (Day 1 of Cycle 2), Day 29 (Day 1 of Cycle 3)

Population: The analysis was performed in pharmacokinetic (PK) set population defined as all safety set participants who had at least one valid (measurable) PK sample of midostaurin, and who had no significant restricted co-medications.

The plasma concentrations of midostaurin (PKC412) and its two major metabolites, CGP62221 and CGP52421 were determined by using a validated liquid chromatography/tandem mass spectrometry method.

Outcome measures

SECONDARY outcome

Timeframe: Baseline (start of study treatment) up to End of treatment (up to 24 months after last dose or until death whichever occurred first)

Population: The analysis was performed in safety set population, defined as the participants who received at least one dose of midostaurin.

An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the participant or require medical or surgical intervention to prevent one of the aforementioned outcomes. Treatment related AEs or SAEs were defined as AEs or SAEs that were suspected to be related to study treatment as per investigator. On treatment death was a fatal event leading to permanent cessations of all vital functions of the body.

Outcome measures

Outcome measures
Measure	Cohort 1: Midostaurin (30 Milligrams/Meters^2) n=7 Participants Participants received bodyweight and BSA stratified dose of midostaurin 30 mg/m\^2 bid through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.	Cohort 2: Midostaurin (60 mg/m^2) n=15 Participants Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m\^2 bid through oral route. The total daily dose in 60 mg/m\^2 bid cohort was 120 mg/m\^2.
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs or SAEs and Death During the Study AEs	6 Participants	15 Participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs or SAEs and Death During the Study AEs suspected to be drug related	1 Participants	2 Participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs or SAEs and Death During the Study On-treatment death	2 Participants	3 Participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs or SAEs and Death During the Study SAEs	3 Participants	6 Participants
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs or SAEs and Death During the Study SAEs suspected to be drug related	0 Participants	1 Participants

Adverse Events

Cohort 1: Midostaurin (30 Milligrams/Meters^2)

Serious events: 3 serious events

Other events: 6 other events

Deaths: 0 deaths

Cohort 2: Midostaurin (60 mg/m^2)

Serious events: 6 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

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 the pooled data (i.e, data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Cohort 1: Midostaurin (30 Milligrams/Meters^2) n=7 Participants Participants received bodyweight and BSA stratified dose of midostaurin 30 mg/m\^2 bid through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.	Cohort 2: Midostaurin (60 mg/m^2) n=15 Participants Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m\^2 bid through oral route. The total daily dose in 60 mg/m\^2 bid cohort was 120 mg/m\^2.
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP52421-Cycle 1/Day 7 (0 hour)	1269 nanograms/milliliters (ng/mL) Standard Deviation 453.963	2129 nanograms/milliliters (ng/mL) Standard Deviation 341.97
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 PKC412-Cycle 1/Day 1 (1 hour)	1678 nanograms/milliliters (ng/mL) Standard Deviation 652.817	2330.88 nanograms/milliliters (ng/mL) Standard Deviation 1290.136
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 PKC412-Cycle 1/Day 1 (2 hour)	1762.5 nanograms/milliliters (ng/mL) Standard Deviation 226.771	2449.09 nanograms/milliliters (ng/mL) Standard Deviation 936.039
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 PKC412-Cycle 1/Day 1 (3 hour)	1891.67 nanograms/milliliters (ng/mL) Standard Deviation 505.941	2287.5 nanograms/milliliters (ng/mL) Standard Deviation 1421.365
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 PKC412-Cycle 1/Day 1 (12 hour)	939.17 nanograms/milliliters (ng/mL) Standard Deviation 347.925	2068.85 nanograms/milliliters (ng/mL) Standard Deviation 2183.946
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 PKC412-Cycle 1/Day 5 (0 hour)	2444 nanograms/milliliters (ng/mL) Standard Deviation 936.659	2610.1 nanograms/milliliters (ng/mL) Standard Deviation 2480.716
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 PKC412-Cycle 1/Day 7 (0 hour)	1945 nanograms/milliliters (ng/mL) Standard Deviation 643.467	2028 nanograms/milliliters (ng/mL) Standard Deviation 2071.949
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 PKC412-Cycle 2/Day 1 (0 hour)	1832.5 nanograms/milliliters (ng/mL) Standard Deviation 773.881	726 nanograms/milliliters (ng/mL) Standard Deviation 379.953
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 PKC412-Cycle 3/Day 1 (0 hour)	962 nanograms/milliliters (ng/mL) Standard Deviation 505.146	674 nanograms/milliliters (ng/mL) Standard Deviation 340.776
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP62221-Cycle 1/Day 1 (1 hour)	106.18 nanograms/milliliters (ng/mL) Standard Deviation 89.473	228.33 nanograms/milliliters (ng/mL) Standard Deviation 148.469
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP62221-Cycle 1/Day 1 (2 hour)	208.95 nanograms/milliliters (ng/mL) Standard Deviation 183.22	458.75 nanograms/milliliters (ng/mL) Standard Deviation 281.882
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP62221-Cycle 1/Day 1 (3 hour)	333.4 nanograms/milliliters (ng/mL) Standard Deviation 227.863	563.63 nanograms/milliliters (ng/mL) Standard Deviation 276.938
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP62221-Cycle 1/Day 1 (12 hour)	424.35 nanograms/milliliters (ng/mL) Standard Deviation 299.416	730.31 nanograms/milliliters (ng/mL) Standard Deviation 385.698
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP62221-Cycle 1/Day 5 (0 hour)	3182 nanograms/milliliters (ng/mL) Standard Deviation 1756.778	3360.3 nanograms/milliliters (ng/mL) Standard Deviation 2002.498
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP62221-Cycle 1/Day 7 (0 hour)	3390 nanograms/milliliters (ng/mL) Standard Deviation 1400.071	2895 nanograms/milliliters (ng/mL) Standard Deviation 1893.347
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP62221-Cycle 2/Day 1 (0 hour)	2380 nanograms/milliliters (ng/mL) Standard Deviation 728.331	1614.14 nanograms/milliliters (ng/mL) Standard Deviation 1057.585
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP62221-Cycle 3/Day 1 (0 hour)	1140.67 nanograms/milliliters (ng/mL) Standard Deviation 189.16	1759.2 nanograms/milliliters (ng/mL) Standard Deviation 923.668
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP52421-Cycle 1/Day 1 (1 hour)	71.64 nanograms/milliliters (ng/mL) Standard Deviation 42.325	111.58 nanograms/milliliters (ng/mL) Standard Deviation 78.187
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP52421-Cycle 1/Day 1 (2 hour)	113.23 nanograms/milliliters (ng/mL) Standard Deviation 54.831	189.65 nanograms/milliliters (ng/mL) Standard Deviation 128.879
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP52421-Cycle 1/Day 1 (3 hour)	152.18 nanograms/milliliters (ng/mL) Standard Deviation 78.405	236.19 nanograms/milliliters (ng/mL) Standard Deviation 144.723
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP52421-Cycle 1/Day 1 (12 hour)	139.27 nanograms/milliliters (ng/mL) Standard Deviation 68.198	259.52 nanograms/milliliters (ng/mL) Standard Deviation 148.943
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP52421-Cycle 1/Day 5 (0 hour)	1018 nanograms/milliliters (ng/mL) Standard Deviation 259.014	1581 nanograms/milliliters (ng/mL) Standard Deviation 509.208
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP52421-Cycle 2/Day 1 (0 hour)	2350 nanograms/milliliters (ng/mL) Standard Deviation 1110.465	2640 nanograms/milliliters (ng/mL) Standard Deviation 541.018
Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 CGP52421-Cycle 3/Day 1 (0 hour)	2386.67 nanograms/milliliters (ng/mL) Standard Deviation 277.909	3488 nanograms/milliliters (ng/mL) Standard Deviation 1511.529

Measure	Cohort 1: Midostaurin (30 Milligrams/Meters^2) n=7 participants at risk Participants received bodyweight and BSA stratified dose of midostaurin 30 mg/m\^2 bid through oral route. The total daily dose in 30 mg/m\^2 bid cohort was 60 mg/m\^2.	Cohort 2: Midostaurin (60 mg/m^2) n=15 participants at risk Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m\^2 bid through oral route. The total daily dose in 60 mg/m\^2 bid cohort was 120 mg/m\^2.
Blood and lymphatic system disorders Febrile Neutropenia	14.3% 1/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	6.7% 1/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Blood and lymphatic system disorders Neutropenia	14.3% 1/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	0.00% 0/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Gastrointestinal disorders Diarrhoea	14.3% 1/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	6.7% 1/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Gastrointestinal disorders Tongue Oedema	0.00% 0/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	6.7% 1/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Gastrointestinal disorders Vomiting	14.3% 1/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	6.7% 1/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
General disorders Pyrexia	14.3% 1/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	0.00% 0/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Immune system disorders Cytokine Release Syndrome	0.00% 0/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	6.7% 1/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Infections and infestations Infection	14.3% 1/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	0.00% 0/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Infections and infestations Pneumonia	0.00% 0/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	6.7% 1/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Injury, poisoning and procedural complications Tongue Injury	0.00% 0/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	6.7% 1/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Investigations Alanine Aminotransferase Increased	0.00% 0/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	6.7% 1/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Investigations Blast Cell Count Increased	0.00% 0/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	6.7% 1/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Metabolism and nutrition disorders Hypophagia	14.3% 1/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	0.00% 0/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Metabolism and nutrition disorders Malnutrition	0.00% 0/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	6.7% 1/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Musculoskeletal and connective tissue disorders Bone Pain	0.00% 0/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	6.7% 1/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Nervous system disorders Headache	14.3% 1/7 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks	0.00% 0/15 • Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks