A Phase I Clinical Study With Investigational Compound LTT462 in Adult Patients With Specific Advanced Cancers.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02711345
• Collaborator: (none)
• Enrollment: 65
• Locations: 7
• Arms: 5
• Actual Duration (Months): 31.2
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

A phase I study of LTT462 in patients with advanced solid tumors that harbor MAPK pathway alterations.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Neoplasms; Non-Small-Cell Lung Carcinoma; Melanoma; Other Solid Tumors	Drug: LTT462	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Dose Finding Study of Oral LTT462 in Adult Patients With Advanced Solid Tumors Harboring MAPK Pathway Alterations.
• Actual Study Start Date: Apr 15, 2016
• Actual Primary Completion Date: Nov 21, 2018
• Actual Study Completion Date: Nov 21, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Escalation	Drug: LTT462; ERK Inhibitor
Experimental: Expansion Group 1	Drug: LTT462; ERK Inhibitor
Experimental: Expansion Group 2	Drug: LTT462; ERK Inhibitor
Experimental: Expansion Group 3	Drug: LTT462; ERK Inhibitor
Experimental: Expansion Group 4	Drug: LTT462; ERK Inhibitor

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up to 2.8 years]

   An adverse events is defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions that occur after participant's signed informed consent has been obtained. A SAE is described as any adverse event that leads to death, is life threatening, causes or prolongs hospitalization, results in a congenital anomaly, or any other important medical event not described above.

2. Percentage of Participants With Dose Limiting Toxicities (DLTs) [Up to 2.8 years]

   Percentage of participants with dose limiting toxicity were reported.

3. Percentage of Participants With at Least One Dose Reduction [Up to 2.8 years]

   Percentage of participants with at least one dose reduction were reported.

4. Percentage of Participants With at Least One Dose Interruptions [Up to 2.8 years]

   Percentage of participants with at least dose interruptions were reported.

5. Dose Intensity Received by Participants [Up to 2.8 years]

   Dose intensity of LTT462 received by treatment group was reported.

Secondary Outcome Measures

1. Percentage of Participants With Overall Response Rate (ORR) [Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)]

   Percentage of participants with overall response rate were reported.

2. Percentage of Participants With Disease Control Rate (DCR) [Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)]

   Percentage of participants with disease control rate were reported.

3. Duration of Response (DOR) [Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)]

   DOR is defined as the time between the date of the first documented response (complete response [CR] or partial response [PR]) and the date of progression.

4. Progression Free Survival (PFS) [Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)]

   Median time for progression free survival was reported.

5. Overall Survival (OS) - Only for Dose Expansion Phase [Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)]

   Median time for overall survival, only for dose expansion phase was reported.

6. The Maximum (Peak) Observed Plasma, Blood, Serum, or Other Body Fluid Drug Concentration (Cmax) After Single Dose Administration of LTT462 [day 1, day 15]

   Cmax is the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration expressed in mass x volume-1.

7. Area Under the Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of LTT462 [Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1]

   AUClast is the area under the curve from time zero to the last measurable concentration sampling time calculated by mass * time *volume^-1

8. The Time to Reach Maximum (Peak) Plasma, Blood, Serum, or Other Body Fluid Drug Concentration (Tmax) After Single Dose Administration of LTT462 [day 1, day 15]

   Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration.

9. Elimination Half-life (T1/2) of LTT462 [Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1]

   T1/2 is the Elimination half-life.

10. The Area Under the Curve Calculated to the End of a Dosing Interval (Tau) at Steady-state (AUCtau) of LTT462 [Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1]

    AUCtau is the area under the curve calculated to the end of a dosing interval (tau) at steady-state calculated by formula amount *time * volume^-1

11. Accumulation Ratio (Racc) of LTT462 [Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1]

    Racc is the accumulation ratio calculated by AUCtau ratio Day 15 versus Day 1.

12. Changes From Baseline in Relative Quantity (RQ) of Dual Specificity Phosphatase 6 (DUSP6) in Tumor Tissue and in Blood [Cycle 1 Days 1, 2, 3, 15 and 16]

    Assessment of Pharmacodynamic (PD) effects of LTT462 in tumor, pre- and post- treatment tumor biopsies were examined for expression of DUSP6. For assessment of PD effects in blood, levels of DUSP6 were measured in blood samples.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient (male or female) ≥12 years of age

• ECOG (Eastern Cooperative Oncology Group) performance status ≤1

• Must have progressed following standard therapy, or for whom, in the opinion of the Investigator, no effective standard therapy exists, is tolerated or appropriate.

• Patients must be willing and able to undergo study required biopsies.

• Presence of at least one measurable lesion according to RECIST v1.1.

• Documented MAPK pathway alteration

Exclusion Criteria:

• Prior treatment with ERK inhibitors.

• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO.

• Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.

• Patients receiving proton pump inhibitors (PPI) which cannot be discontinued 3 days prior to the start study treatment and for the duration of the study.

• Patients with malignant disease other than that being treated in the study.

• Clinically significant cardiac disease.

Other protocol-defined exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	New York	New York	United States	10065
2	Novartis Investigative Site	Houston	Texas	United States	77030-4009
3	Novartis Investigative Site	Essen		Germany	45147
4	Novartis Investigative Site	Chuo ku	Tokyo	Japan	104 0045
5	Novartis Investigative Site	Singapore		Singapore	169610
6	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
7	Novartis Investigative Site	Bellinzona		Switzerland	6500

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Mar 13, 2018
• Statistical Analysis Plan - May 13, 2019

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02711345
• Other Study ID Numbers: CLTT462X2101; 2015-003614-24
• First Posted: Mar 17, 2016
• Last Update Posted: Sep 19, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: LTT462; ERK; MAPK; solid tumor
• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung; Ovarian Neoplasms

Study Results

Participant Flow

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received LTT462 45 milligram (mg) once daily (QD)	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Period Title: Overall Study
STARTED	2	3	6	4	8	6	12	6	6	12
COMPLETED	0	0	0	0	0	0	0	0	0	0
NOT COMPLETED	2	3	6	4	8	6	12	6	6	12

Baseline Characteristics

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID	Total
Arm/Group Description	Participants received 45 mg LTT462 once QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 BID as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.	Total of all reporting groups
Overall Participants	2	3	6	4	8	6	12	6	6	12	65
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	1 12.5%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.5%
Between 18 and 65 years	1 50%	2 66.7%	5 83.3%	3 75%	5 62.5%	5 83.3%	7 58.3%	5 83.3%	5 83.3%	6 50%	44 67.7%
>=65 years	1 50%	1 33.3%	1 16.7%	1 25%	2 25%	1 16.7%	5 41.7%	1 16.7%	1 16.7%	6 50%	20 30.8%
Sex: Female, Male (Count of Participants)
Female	1 50%	3 100%	4 66.7%	2 50%	6 75%	4 66.7%	5 41.7%	4 66.7%	4 66.7%	7 58.3%	40 61.5%
Male	1 50%	0 0%	2 33.3%	2 50%	2 25%	2 33.3%	7 58.3%	2 33.3%	2 33.3%	5 41.7%	25 38.5%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	1 50%	2 66.7%	5 83.3%	2 50%	6 75%	2 33.3%	7 58.3%	4 66.7%	5 83.3%	8 66.7%	42 64.6%
Black	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 16.7%	0 0%	2 16.7%	3 4.6%
Asian	1 50%	1 33.3%	1 16.7%	1 25%	1 12.5%	3 50%	4 33.3%	0 0%	0 0%	2 16.7%	14 21.5%
Unknown	00 0%	0 0%	0 0%	1 25%	1 12.5%	1 16.7%	1 8.3%	1 16.7%	1 16.7%	0 0%	6 9.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An adverse events is defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions that occur after participant's signed informed consent has been obtained. A SAE is described as any adverse event that leads to death, is life threatening, causes or prolongs hospitalization, results in a congenital anomaly, or any other important medical event not described above.
Time Frame	Up to 2.8 years

Outcome Measure Data

Analysis Population Description

The safety set included all participants who had received at least one dose of LTT462.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 BID as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	2	3	6	4	8	6	12	6	6	12
AEs	2 100%	3 100%	6 100%	4 100%	8 100%	6 100%	12 100%	5 83.3%	6 100%	12 100%
SAEs	1 50%	0 0%	3 50%	1 25%	5 62.5%	1 16.7%	8 66.7%	4 66.7%	3 50%	5 41.7%

2. Primary Outcome

Title	Percentage of Participants With Dose Limiting Toxicities (DLTs)
Description	Percentage of participants with dose limiting toxicity were reported.
Time Frame	Up to 2.8 years

Outcome Measure Data

Analysis Population Description

The dose determining set included all participants from the safety set enrolled in the escalation part of the study who, during the first 28 days of dosing, had received at least 75 percent of the planned daily doses of LTT462 and had had sufficient safety evaluations, or had experienced a DLT.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 once QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 BID as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	2	3	6	4	7	4	7	3	4	9
Number [Percentage of participants]	0 0%	0 0%	16.7 278.3%	25.0 625%	0 0%	0 0%	28.6 238.3%	100 1666.7%	0 0%	44.4 370%

3. Primary Outcome

Title	Percentage of Participants With at Least One Dose Reduction
Description	Percentage of participants with at least one dose reduction were reported.
Time Frame	Up to 2.8 years

Outcome Measure Data

Analysis Population Description

The safety set included all participants who had received at least one dose of LTT462.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	2	3	6	4	8	6	12	6	6	12
Number [Percentage of participants]	0 0%	0 0%	16.7 278.3%	0 0%	0 0%	0 0%	16.7 139.2%	33.3 555%	16.7 278.3%	33.3 277.5%

4. Primary Outcome

Title	Percentage of Participants With at Least One Dose Interruptions
Description	Percentage of participants with at least dose interruptions were reported.
Time Frame	Up to 2.8 years

Outcome Measure Data

Analysis Population Description

The safety set included all participants who had received at least one dose of LTT462.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	2	3	6	4	8	6	12	6	6	12
Number [Percentage of participants]	100 5000%	100 3333.3%	100 1666.7%	100 2500%	100 1250%	100 1666.7%	100 833.3%	100 1666.7%	100 1666.7%	100 833.3%

5. Primary Outcome

Title	Dose Intensity Received by Participants
Description	Dose intensity of LTT462 received by treatment group was reported.
Time Frame	Up to 2.8 years

Outcome Measure Data

Analysis Population Description

The safety set included all participants who had received at least one dose of LTT462.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	2	3	6	4	8	6	12	6	6	12
Mean (Standard Deviation) [milligram per day (mg/day)]	65.3 (28.74)	98.1 (3.21)	133.9 (21.84)	200.0 (0.00)	272.7 (30.90)	326.7 (81.54)	409.2 (64.88)	468.2 (171.48)	131.6 (22.08)	178.0 (35.32)

6. Secondary Outcome

Title	Percentage of Participants With Overall Response Rate (ORR)
Description	Percentage of participants with overall response rate were reported.
Time Frame	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)

Outcome Measure Data

Analysis Population Description

The full analysis set included all participants who had received at least one dose of LTT462.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	2	3	6	4	8	6	12	6	6	12
Number (95% Confidence Interval) [Percentage of participants]	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

7. Secondary Outcome

Title	Percentage of Participants With Disease Control Rate (DCR)
Description	Percentage of participants with disease control rate were reported.
Time Frame	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)

Outcome Measure Data

Analysis Population Description

The full analysis set included all participants who had received at least one dose of LTT462.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	2	3	6	4	8	6	12	6	6	12
Number (95% Confidence Interval) [Percentage of participants]	50.0 2500%	0 0%	0 0%	0 0%	37.5 468.8%	16.7 278.3%	8.3 69.2%	16.7 278.3%	16.7 278.3%	0 0%

8. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR is defined as the time between the date of the first documented response (complete response [CR] or partial response [PR]) and the date of progression.
Time Frame	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)

Outcome Measure Data

Analysis Population Description

As there were no participant achieving response (CR or PR) during escalation phase of the study (only stable disease was achieved). Therefore the evaluation of duration of response could not be performed.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	0	0	0	0	0	0	0	0	0	0

9. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Median time for progression free survival was reported.
Time Frame	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)

Outcome Measure Data

Analysis Population Description

The full analysis set included all participants who had received at least one dose of LTT462.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	2	3	6	4	8	6	12	6	6	12
Median (95% Confidence Interval) [months]	5.3	1.6	1.7	1.9	1.8	2.1	0.9	1.4	1.5	1.6

10. Secondary Outcome

Title	Overall Survival (OS) - Only for Dose Expansion Phase
Description	Median time for overall survival, only for dose expansion phase was reported.
Time Frame	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)

Outcome Measure Data

Analysis Population Description

Overall survival was not evaluated because the study ended before enrolling into the dose-expansion part.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	0	0	0	0	0	0	0	0	0	0

11. Secondary Outcome

Title	The Maximum (Peak) Observed Plasma, Blood, Serum, or Other Body Fluid Drug Concentration (Cmax) After Single Dose Administration of LTT462
Description	Cmax is the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration expressed in mass x volume-1.
Time Frame	day 1, day 15

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set (PAS) included of all participants who have at least 1 PK blood sample providing measurable LTT462 and received at least 1 dose of study drug, didn't vomit within 4 hours postdose, had at least 1 primary PK parameter. Here 'n' number analyzed signifies number of participants who were evaluable at each time point.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	2	3	6	4	8	6	11	4	6	12
Day 1	61.3 (55.9)	134 (38.8)	218 (230.9)	494 (126.8)	717 (127.4)	1580 (60.8)	1420 (83.5)	1280 (47.7)	598 (83.0)	575 (73.8)
Day 15	139 (29.9)	938 (82.5)	707 (69.0)	972 (92.4)	1330 (131.9)	2370 (83.3)	3470 (49.7)	1030 (248.8)	1390 (58.5)	1510 (108.0)

12. Secondary Outcome

Title	Area Under the Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of LTT462
Description	AUClast is the area under the curve from time zero to the last measurable concentration sampling time calculated by mass * time *volume^-1
Time Frame	Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1

Outcome Measure Data

Analysis Population Description

PAS included of all participants who have at least 1 PK blood sample providing measurable LTT462 and received at least 1 dose of study drug, didn't vomit within 4 hours postdose, had at least 1 primary PK parameter. Here 'N' number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	2	3	6	4	7	6	10	3	5	12
Geometric Mean (Geometric Coefficient of Variation) [hour*nanogram per milliliter (h*ng/mL)]	851 (106.0)	2260 (30.0)	3880 (133.6)	10400 (95.4)	12800 (157.4)	23300 (55.5)	23800 (115.3)	11800 (64.2)	9240 (78.3)	7630 (98.8)

13. Secondary Outcome

Title	The Time to Reach Maximum (Peak) Plasma, Blood, Serum, or Other Body Fluid Drug Concentration (Tmax) After Single Dose Administration of LTT462
Description	Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration.
Time Frame	day 1, day 15

Outcome Measure Data

Analysis Population Description

PAS included of all participants who have at least 1 PK blood sample providing measurable LTT462 and received at least 1 dose of study drug, didn't vomit within 4 hours postdose, had at least 1 primary PK parameter. Here 'n' number analyzed signifies number of participants who were evaluable at each time point.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	2	3	6	4	8	6	11	4	6	12
Day 1	2.45	1.98	3.49	5.48	3.08	3.04	3.98	3.95	2.25	3.03
Day 15	5.93	4.02	4.05	3.00	2.59	2.55	2.98	5.25	2.17	2.18

14. Secondary Outcome

Title	Elimination Half-life (T1/2) of LTT462
Description	T1/2 is the Elimination half-life.
Time Frame	Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1

Outcome Measure Data

Analysis Population Description

PAS included of all participants who have at least 1 PK blood sample providing measurable LTT462 and received at least 1 dose of study drug, didn't vomit within 4 hours postdose, had at least 1 primary PK parameter. Here 'N' number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	1	2	4	2	3	6	7	2	2	9
Median (Full Range) [hour]	27.9	39.2	20.8	16.8	15.2	14.0	17.6	13.2	16.2	17.1

15. Secondary Outcome

Title	The Area Under the Curve Calculated to the End of a Dosing Interval (Tau) at Steady-state (AUCtau) of LTT462
Description	AUCtau is the area under the curve calculated to the end of a dosing interval (tau) at steady-state calculated by formula amount *time * volume^-1
Time Frame	Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1

Outcome Measure Data

Analysis Population Description

PAS included of all participants who have at least 1 PK blood sample providing measurable LTT462 and received at least 1 dose of study drug, didn't vomit within 4 hours postdose, had at least 1 primary PK parameter. Here 'N' number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	1	1	4	3	5	4	4	1	5	4
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	3010 (NA)	6370 (NA)	8660 (50.0)	14600 (96.5)	13100 (81.6)	25400 (74.3)	35400 (94.8)	6760 (NA)	11100 (59.5)	18600 (85.2)

16. Secondary Outcome

Title	Accumulation Ratio (Racc) of LTT462
Description	Racc is the accumulation ratio calculated by AUCtau ratio Day 15 versus Day 1.
Time Frame	Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1

Outcome Measure Data

Analysis Population Description

PAS included of all participants who have at least 1 PK blood sample providing measurable LTT462 and received at least 1 dose of study drug, didn't vomit within 4 hours postdose, had at least 1 primary PK parameter. Here 'N' number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	1	1	4	3	4	4	3	0	4	4
Geometric Mean (Geometric Coefficient of Variation) [Ratio]	3.01 (NA)	3.35 (NA)	5.09 (72.7)	2.74 (46.9)	1.49 (25.1)	1.73 (62.4)	1.44 (73.4)	3.19 (50.2)	6.89 (84.3)

17. Secondary Outcome

Title	Changes From Baseline in Relative Quantity (RQ) of Dual Specificity Phosphatase 6 (DUSP6) in Tumor Tissue and in Blood
Description	Assessment of Pharmacodynamic (PD) effects of LTT462 in tumor, pre- and post- treatment tumor biopsies were examined for expression of DUSP6. For assessment of PD effects in blood, levels of DUSP6 were measured in blood samples.
Time Frame	Cycle 1 Days 1, 2, 3, 15 and 16

Outcome Measure Data

Analysis Population Description

The full analysis set included all participants who had received at least one dose of LTT462.

Arm/Group Title	LTT462 45 mg QD	LTT462 100 mg QD	LTT462 150 mg QD	LTT462 200 mg QD	LTT462 300 mg QD	LTT462 400 mg QD	LTT462 450 mg QD	LTT462 600 mg QD	LTT462 150 mg BID	LTT462 200 mg BID
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.	Participants received 100 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 QD as oral capsules.	Participants received 200 mg LTT462 QD as oral capsules.	Participants received 300 mg LTT462 QD as oral capsules.	Participants received 400 mg LTT462 QD as oral capsules.	Participants received 450 mg LTT462 QD as oral capsules.	Participants received 600 mg LTT462 QD as oral capsules.	Participants received 150 mg LTT462 twice daily (BID) as oral capsules.	Participants received 200 mg LTT462 BID as oral capsules.
Measure Participants	2	3	6	4	8	6	12	6	6	12
Tumor Sample	-0.2 (NA)	0.8 (1.11)	-1.1 (29.46)	-28.8 (NA)	-31.0 (31.06)	-56.5 (NA)	-22.2 (28.67)	-79.9 (NA)	-61.8 (4.16)	-14.4 (22.27)
Blood Sample	-50.8 (6.14)	-66.1 (40.22)	-35.2 (27.33)	-34.7 (22.02)	-42.5 (16.56)	-43.0 (13.67)	-40.1 (9.92)	-40.4 (21.04)	-39.2 (12.98)	-32.9 (18.71)

Adverse Events

Time Frame	Adverse events were evaluated from screening until at least 30 days after the discontinuation of study treatment (Up to 2.8 years)
Adverse Event Reporting Description	The Safety Set included all participants who had received at least one dose of LTT462.
Arm/Group Title	LTT462 45 mg QD		LTT462 100 mg QD		LTT462 150 mg QD		LTT462 200 mg QD		LTT462 300 mg QD		LTT462 400 mg QD		LTT462 450 mg QD		LTT462 600 mg QD		All QD Participants		LTT462 150 mg BID		LTT462 200 mg BID		All BID Participants
Arm/Group Description	Participants received 45 mg LTT462 QD as oral capsules.		Participants received 100 mg LTT462 QD as oral capsules.		Participants received 150 mg LTT462 QD as oral capsules.		Participants received 200 mg LTT462 QD as oral capsules.		Participants received 300 mg LTT462 QD as oral capsules.		Participants received 400 mg LTT462 QD as oral capsules.		Participants received 450 mg LTT462 QD as oral capsules.		Participants received 450 mg LTT462 QD as oral capsules.		Participants received 45 to 600 mg LTT462 QD as oral capsules.		Participants received 150 mg LTT462 BID as oral capsules.		Participants received 200 mg LTT462 BID as oral capsules.		Participants received 150 and 200 mg LTT462 BID as oral capsules.
All Cause Mortality
	LTT462 45 mg QD		LTT462 100 mg QD		LTT462 150 mg QD		LTT462 200 mg QD		LTT462 300 mg QD		LTT462 400 mg QD		LTT462 450 mg QD		LTT462 600 mg QD		All QD Participants		LTT462 150 mg BID		LTT462 200 mg BID		All BID Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/2 (50%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		2/8 (25%)		1/6 (16.7%)		1/12 (8.3%)		1/6 (16.7%)		6/47 (12.8%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Serious Adverse Events
	LTT462 45 mg QD		LTT462 100 mg QD		LTT462 150 mg QD		LTT462 200 mg QD		LTT462 300 mg QD		LTT462 400 mg QD		LTT462 450 mg QD		LTT462 600 mg QD		All QD Participants		LTT462 150 mg BID		LTT462 200 mg BID		All BID Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/2 (50%)		0/3 (0%)		3/6 (50%)		1/4 (25%)		5/8 (62.5%)		1/6 (16.7%)		8/12 (66.7%)		4/6 (66.7%)		23/47 (48.9%)		3/6 (50%)		5/12 (41.7%)		8/18 (44.4%)
Blood and lymphatic system disorders
Anaemia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Thrombocytopenia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Cardiac disorders
Acute myocardial infarction	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Cardio-respiratory arrest	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Sinus tachycardia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Eye disorders
Retinopathy	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Gastrointestinal disorders
Abdominal pain	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		2/8 (25%)		0/6 (0%)		3/12 (25%)		0/6 (0%)		5/47 (10.6%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Colitis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Diarrhoea	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		2/12 (16.7%)		2/18 (11.1%)
Gastrointestinal haemorrhage	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Ileus	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Nausea	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Upper gastrointestinal haemorrhage	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
General disorders
Fatigue	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		1/6 (16.7%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Gait disturbance	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
General physical health deterioration	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Non-cardiac chest pain	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Swelling	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Infections and infestations
Biliary tract infection	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Peritonitis bacterial	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Pneumonia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Respiratory tract infection	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Sepsis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Staphylococcal infection	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Upper respiratory tract infection	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Investigations
Alanine aminotransferase increased	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Aspartate aminotransferase increased	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Blood creatinine increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Metabolism and nutrition disorders
Dehydration	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		1/6 (16.7%)		1/12 (8.3%)		2/18 (11.1%)
Hyponatraemia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Musculoskeletal pain	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Nervous system disorders
Dizziness	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Renal and urinary disorders
Acute kidney injury	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Glomerulonephritis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Renal injury	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Reproductive system and breast disorders
Vaginal haemorrhage	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/2 (50%)		0/3 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		3/47 (6.4%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Pneumonitis	0/2 (0%)		0/3 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Vascular disorders
Hypotension	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		1/6 (16.7%)		3/47 (6.4%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Vena cava thrombosis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	LTT462 45 mg QD		LTT462 100 mg QD		LTT462 150 mg QD		LTT462 200 mg QD		LTT462 300 mg QD		LTT462 400 mg QD		LTT462 450 mg QD		LTT462 600 mg QD		All QD Participants		LTT462 150 mg BID		LTT462 200 mg BID		All BID Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		3/3 (100%)		6/6 (100%)		4/4 (100%)		8/8 (100%)		6/6 (100%)		12/12 (100%)		5/6 (83.3%)		46/47 (97.9%)		6/6 (100%)		12/12 (100%)		18/18 (100%)
Blood and lymphatic system disorders
Agranulocytosis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Anaemia	0/2 (0%)		2/3 (66.7%)		3/6 (50%)		1/4 (25%)		2/8 (25%)		3/6 (50%)		4/12 (33.3%)		3/6 (50%)		18/47 (38.3%)		1/6 (16.7%)		3/12 (25%)		4/18 (22.2%)
Leukocytosis	1/2 (50%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		2/6 (33.3%)		4/47 (8.5%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Leukopenia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Lymphopenia	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Neutropenia	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		2/47 (4.3%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Thrombocytopenia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		2/8 (25%)		0/6 (0%)		1/12 (8.3%)		1/6 (16.7%)		4/47 (8.5%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Cardiac disorders
Aortic valve incompetence	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Cyanosis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Tricuspid valve incompetence	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Ear and labyrinth disorders
Vertigo	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Endocrine disorders
Goitre	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Eye disorders
Cataract	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Chorioretinopathy	0/2 (0%)		0/3 (0%)		0/6 (0%)		1/4 (25%)		2/8 (25%)		1/6 (16.7%)		2/12 (16.7%)		1/6 (16.7%)		7/47 (14.9%)		0/6 (0%)		2/12 (16.7%)		2/18 (11.1%)
Corneal disorder	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Cystoid macular oedema	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Detachment of retinal pigment epithelium	0/2 (0%)		0/3 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Eye pain	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Macular detachment	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Macular oedema	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		2/12 (16.7%)		2/18 (11.1%)
Retinal detachment	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		1/12 (8.3%)		1/6 (16.7%)		3/47 (6.4%)		2/6 (33.3%)		1/12 (8.3%)		3/18 (16.7%)
Retinal pigment epitheliopathy	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Retinopathy	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		2/12 (16.7%)		1/6 (16.7%)		4/47 (8.5%)		0/6 (0%)		3/12 (25%)		3/18 (16.7%)
Vision blurred	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		3/12 (25%)		0/6 (0%)		4/47 (8.5%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Visual impairment	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Gastrointestinal disorders
Abdominal distension	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		3/47 (6.4%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Abdominal pain	0/2 (0%)		0/3 (0%)		2/6 (33.3%)		0/4 (0%)		1/8 (12.5%)		2/6 (33.3%)		1/12 (8.3%)		0/6 (0%)		6/47 (12.8%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Abdominal pain lower	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Abdominal pain upper	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		1/6 (16.7%)		1/12 (8.3%)		2/18 (11.1%)
Ascites	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		2/6 (33.3%)		0/12 (0%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Constipation	0/2 (0%)		1/3 (33.3%)		3/6 (50%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		1/12 (8.3%)		0/6 (0%)		6/47 (12.8%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Diarrhoea	0/2 (0%)		3/3 (100%)		2/6 (33.3%)		1/4 (25%)		4/8 (50%)		4/6 (66.7%)		5/12 (41.7%)		3/6 (50%)		22/47 (46.8%)		1/6 (16.7%)		5/12 (41.7%)		6/18 (33.3%)
Diverticulum intestinal	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Dry mouth	0/2 (0%)		1/3 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Dyspepsia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Faeces soft	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Flatulence	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Gastritis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Gingival bleeding	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Gingival pain	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Ileus	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Melaena	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Nausea	1/2 (50%)		3/3 (100%)		2/6 (33.3%)		1/4 (25%)		4/8 (50%)		3/6 (50%)		3/12 (25%)		4/6 (66.7%)		21/47 (44.7%)		3/6 (50%)		4/12 (33.3%)		7/18 (38.9%)
Odynophagia	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Proctalgia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Rectal haemorrhage	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Stomatitis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Vomiting	0/2 (0%)		0/3 (0%)		3/6 (50%)		1/4 (25%)		4/8 (50%)		3/6 (50%)		4/12 (33.3%)		4/6 (66.7%)		19/47 (40.4%)		3/6 (50%)		4/12 (33.3%)		7/18 (38.9%)
General disorders
Asthenia	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		1/4 (25%)		1/8 (12.5%)		1/6 (16.7%)		1/12 (8.3%)		0/6 (0%)		5/47 (10.6%)		1/6 (16.7%)		1/12 (8.3%)		2/18 (11.1%)
Face oedema	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Fatigue	0/2 (0%)		1/3 (33.3%)		1/6 (16.7%)		1/4 (25%)		2/8 (25%)		0/6 (0%)		1/12 (8.3%)		2/6 (33.3%)		8/47 (17%)		2/6 (33.3%)		4/12 (33.3%)		6/18 (33.3%)
General physical health deterioration	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Malaise	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Mucosal dryness	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Mucosal haemorrhage	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Non-cardiac chest pain	1/2 (50%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Oedema peripheral	1/2 (50%)		0/3 (0%)		1/6 (16.7%)		1/4 (25%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		2/6 (33.3%)		6/47 (12.8%)		0/6 (0%)		2/12 (16.7%)		2/18 (11.1%)
Pain	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Peripheral swelling	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		2/12 (16.7%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Pyrexia	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		2/12 (16.7%)		1/6 (16.7%)		4/47 (8.5%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Swelling	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Hepatobiliary disorders
Hepatosplenomegaly	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hyperbilirubinaemia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		1/6 (16.7%)		1/12 (8.3%)		2/18 (11.1%)
Jaundice	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Pneumobilia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Portal vein thrombosis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Infections and infestations
Conjunctivitis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Cystitis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Device related infection	1/2 (50%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Furuncle	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Influenza	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Pneumonia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Rash pustular	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Sinusitis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Skin infection	0/2 (0%)		0/3 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Tonsillitis	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Urinary tract infection	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Injury, poisoning and procedural complications
Procedural dizziness	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Skin abrasion	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Urostomy complication	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Investigations
Alanine aminotransferase increased	2/2 (100%)		0/3 (0%)		2/6 (33.3%)		0/4 (0%)		2/8 (25%)		0/6 (0%)		1/12 (8.3%)		2/6 (33.3%)		9/47 (19.1%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Ammonia increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Amylase increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		1/6 (16.7%)		2/47 (4.3%)		0/6 (0%)		3/12 (25%)		3/18 (16.7%)
Aspartate aminotransferase increased	2/2 (100%)		1/3 (33.3%)		2/6 (33.3%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		1/12 (8.3%)		2/6 (33.3%)		10/47 (21.3%)		2/6 (33.3%)		3/12 (25%)		5/18 (27.8%)
Bilirubin conjugated increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Blood alkaline phosphatase increased	0/2 (0%)		3/3 (100%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		2/6 (33.3%)		1/12 (8.3%)		1/6 (16.7%)		7/47 (14.9%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Blood bilirubin increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		1/6 (16.7%)		1/12 (8.3%)		2/18 (11.1%)
Blood creatine phosphokinase increased	1/2 (50%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		2/8 (25%)		0/6 (0%)		4/12 (33.3%)		0/6 (0%)		7/47 (14.9%)		0/6 (0%)		3/12 (25%)		3/18 (16.7%)
Blood creatinine increased	0/2 (0%)		1/3 (33.3%)		2/6 (33.3%)		1/4 (25%)		1/8 (12.5%)		1/6 (16.7%)		1/12 (8.3%)		2/6 (33.3%)		9/47 (19.1%)		0/6 (0%)		2/12 (16.7%)		2/18 (11.1%)
Blood lactate dehydrogenase increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Blood potassium increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Blood triglycerides increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Blood urea increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
C-reactive protein increased	1/2 (50%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		2/6 (33.3%)		4/47 (8.5%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Eosinophil count increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Gamma-glutamyltransferase	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Gamma-glutamyltransferase increased	0/2 (0%)		1/3 (33.3%)		1/6 (16.7%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		1/12 (8.3%)		2/6 (33.3%)		7/47 (14.9%)		0/6 (0%)		2/12 (16.7%)		2/18 (11.1%)
Granulocyte count increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
International normalised ratio increased	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Lipase	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Lipase increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		2/12 (16.7%)		2/18 (11.1%)
Liver function test	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Lymphocyte count decreased	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Platelet count decreased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Troponin increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
White blood cell count increased	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/2 (0%)		1/3 (33.3%)		3/6 (50%)		1/4 (25%)		2/8 (25%)		3/6 (50%)		1/12 (8.3%)		3/6 (50%)		14/47 (29.8%)		0/6 (0%)		3/12 (25%)		3/18 (16.7%)
Dehydration	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		1/6 (16.7%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hyperalbuminaemia	0/2 (0%)		1/3 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hyperamylasaemia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hypercalcaemia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Hyperglycaemia	0/2 (0%)		0/3 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hyperkalaemia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		1/6 (16.7%)		2/47 (4.3%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Hyperlipasaemia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hypernatraemia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		2/6 (33.3%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hyperphosphataemia	0/2 (0%)		0/3 (0%)		0/6 (0%)		1/4 (25%)		1/8 (12.5%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		3/47 (6.4%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hypertriglyceridaemia	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Hyperuricaemia	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hypoalbuminaemia	0/2 (0%)		1/3 (33.3%)		2/6 (33.3%)		1/4 (25%)		2/8 (25%)		1/6 (16.7%)		1/12 (8.3%)		0/6 (0%)		8/47 (17%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Hypocalcaemia	0/2 (0%)		1/3 (33.3%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		1/12 (8.3%)		0/6 (0%)		4/47 (8.5%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hypokalaemia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hypomagnesaemia	0/2 (0%)		1/3 (33.3%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		3/47 (6.4%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hyponatraemia	0/2 (0%)		1/3 (33.3%)		0/6 (0%)		0/4 (0%)		2/8 (25%)		2/6 (33.3%)		0/12 (0%)		0/6 (0%)		5/47 (10.6%)		3/6 (50%)		1/12 (8.3%)		4/18 (22.2%)
Hypophosphataemia	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/12 (0%)		1/6 (16.7%)		3/47 (6.4%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Back pain	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Groin pain	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Joint swelling	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Muscle tightness	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Musculoskeletal pain	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Myalgia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Pain in extremity	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Lipoma	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Tumour associated fever	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Tumour pain	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Nervous system disorders
Dizziness	0/2 (0%)		1/3 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Dysgeusia	0/2 (0%)		0/3 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Headache	0/2 (0%)		1/3 (33.3%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		3/47 (6.4%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Hypotonia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Loss of consciousness	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Seizure	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Syncope	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Visual field defect	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Psychiatric disorders
Anxiety	1/2 (50%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Delirium	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Depression	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Insomnia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		1/12 (8.3%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Renal and urinary disorders
Haematuria	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Hydronephrosis	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Nephritis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Proteinuria	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Renal failure	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Reproductive system and breast disorders
Genital haemorrhage	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Metrorrhagia	0/2 (0%)		1/3 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Prostatic calcification	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/2 (0%)		1/3 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		1/12 (8.3%)		1/6 (16.7%)		4/47 (8.5%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Dyspnoea	0/2 (0%)		0/3 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		2/47 (4.3%)		1/6 (16.7%)		0/12 (0%)		1/18 (5.6%)
Dyspnoea exertional	0/2 (0%)		1/3 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Epistaxis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Pleural effusion	1/2 (50%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Pulmonary arterial hypertension	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Skin and subcutaneous tissue disorders
Acne	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		2/47 (4.3%)		1/6 (16.7%)		1/12 (8.3%)		2/18 (11.1%)
Alopecia	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		2/12 (16.7%)		2/18 (11.1%)
Decubitus ulcer	1/2 (50%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Dermatitis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Dermatitis acneiform	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		2/8 (25%)		3/6 (50%)		1/12 (8.3%)		0/6 (0%)		6/47 (12.8%)		0/6 (0%)		2/12 (16.7%)		2/18 (11.1%)
Dermatitis exfoliative generalised	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Dry skin	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		2/12 (16.7%)		1/6 (16.7%)		3/47 (6.4%)		0/6 (0%)		2/12 (16.7%)		2/18 (11.1%)
Eczema	0/2 (0%)		1/3 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Erythema	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hyperkeratosis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Night sweats	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Pain of skin	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		0/47 (0%)		0/6 (0%)		1/12 (8.3%)		1/18 (5.6%)
Palmar-plantar erythrodysaesthesia syndrome	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Petechiae	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Pruritus	0/2 (0%)		0/3 (0%)		2/6 (33.3%)		0/4 (0%)		2/8 (25%)		2/6 (33.3%)		2/12 (16.7%)		0/6 (0%)		8/47 (17%)		2/6 (33.3%)		2/12 (16.7%)		4/18 (22.2%)
Purpura	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Rash	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		2/4 (50%)		3/8 (37.5%)		2/6 (33.3%)		5/12 (41.7%)		1/6 (16.7%)		14/47 (29.8%)		4/6 (66.7%)		3/12 (25%)		7/18 (38.9%)
Rash erythematous	0/2 (0%)		1/3 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Rash macular	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Rash maculo-papular	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		2/8 (25%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		3/47 (6.4%)		0/6 (0%)		2/12 (16.7%)		2/18 (11.1%)
Rash papular	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/12 (8.3%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Urticaria	0/2 (0%)		1/3 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Vascular disorders
Deep vein thrombosis	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hypertension	0/2 (0%)		0/3 (0%)		1/6 (16.7%)		1/4 (25%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		1/6 (16.7%)		4/47 (8.5%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Hypotension	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		1/6 (16.7%)		2/47 (4.3%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Pelvic venous thrombosis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Vena cava thrombosis	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/12 (0%)		1/6 (16.7%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)
Venous thrombosis limb	0/2 (0%)		0/3 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/12 (0%)		0/6 (0%)		1/47 (2.1%)		0/6 (0%)		0/12 (0%)		0/18 (0%)

Limitations/Caveats

Following careful evaluation of the available study data and considering the limited clinical activity observed with LTT462, the decision was made to not open the dose expansion phase of the study and the study was terminated early.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.