PKC412 in Participants With Acute Myeloid Leukemia or With Myelodysplastic Syndrome (CPKC412A2104 Core); and PKC412 in Participants With Acute Myeloid Leukemia or With Myelodysplastic Syndrome With Either Wild Type or Mutated FMS-like Tyrosine Kinase 3 (FLT3) (CPKC412A2104E1 and CPKC412A2104E2)

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT00045942

Collaborator

(none)

144

Enrollment

Locations

Arms

73.9

Actual Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

CPKC412A2104 core had a 2 stage design. In stage 1, eight participants were treated. If at least one participant showed a clinical response, four more participants were recruited to stage 2. The trial was to be stopped if no participants showed a response in stage 1. POC was achieved if at least 2 participants out of 12 responded. In PKC412A2104E1, participants with AML or high risk MDS with wild-type or mutant FTL3 who had not previously received a FLT3 inhibitor were randomized to receive continuous twice daily oral doses of either 50 or 100 mg midostaurin in 1 28-day cycle regimen. Participants were to be treated until disease progression or the occurrence of unacceptable treatment-related toxicity. PKC412A2104 E2 contained 2 dosing regimens: 1) intra-participant midostaurin dose escalation and 2) midostaurin with itraconazole in participants with AML and high risk MDS irrespective of FLT3 status. Eligible participants were alternately assigned to the regimens. At the Investigator's discretion, intra-participant dose escalation was allowed for any previously enrolled CPKC412A2104E1 participant receiving midostaurin at the time of the approval of amendment 4. Participants were treated until the time of disease progression.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Myelodysplastic Syndromes	Drug: Itraconazole Drug: PKC412	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

144 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label Phase II (Proof of Concept (POC)) Trial of PKC412 Monotherapy in Participants With Acute Myeloid Leukemia (AML) and Participants With High Risk Myelodysplastic Syndrome (MDS) (CPKC412A2104 Core); An Open-label, Randomized Phase II POC Trial in PKC412 in Participants With AML and Participants With High Risk MDS With Either Wild Type or Mutated FLT3 (CPKC412A2104E1); and An Open-label, Randomized Phase 1/II POC Trial in PKC412 in Participants With AML and Participants With High Risk MDS With Either Wild Type or Mutated FLT3 (CPKC412A2104E2)

Actual Study Start Date :

Jan 30, 2002

Actual Primary Completion Date :

Mar 27, 2008

Actual Study Completion Date :

Mar 27, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PKC412 (Core) Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Drug: PKC412 PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412. Other Names: Midostaurin
Experimental: FLT3 mutated PKC412 100 mg/day (E1) Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Drug: PKC412 PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412. Other Names: Midostaurin
Experimental: FLT3 mutated PKC412 200 mg/day (E1) Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Drug: PKC412 PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412. Other Names: Midostaurin
Experimental: FLT3 wild type PKC412 100 mg/day (E1) Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Drug: PKC412 PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412. Other Names: Midostaurin
Experimental: FLT3 wild type PKC412 200 mg/day (E1) Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Drug: PKC412 PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412. Other Names: Midostaurin
Experimental: FLT3 mutated PKC412 dose escalation Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Drug: PKC412 PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412. Other Names: Midostaurin
Experimental: FLT3 mutated PKC+Itraconazole (E2) Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.	Drug: Itraconazole Itraconazole was commercially available. Drug: PKC412 PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412. Other Names: Midostaurin
Experimental: FLT3 wild type PKC412 dose escalation (E2) Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Drug: PKC412 PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412. Other Names: Midostaurin
Experimental: FLT3 wild type PKC+Itraconazole (E2) Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.	Drug: Itraconazole Itraconazole was commercially available. Drug: PKC412 PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412. Other Names: Midostaurin

Outcome Measures

Primary Outcome Measures

Number of Participants With Best Clinical Response (Core) [from date of first patient first visit (FPFV), 29-Jan-2002, to date of last participant last visit (LPLV), 04-Sep-2003]
Best clinical response was defined as complete response (CR) or partial response (PR), according to NCI definitions for AML and the guidelines for defining responses in MDS.
Percent Decrease in Phospho-FLT3 Compared to Baseline (Core) [days 1, 28]
Number of Participants With Overall Clinical Response (E1) [from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004]
Overall clinical response was defined as CR, PR, minor response (MR) or blast response (BR). CR and PR was defined according to NCI definitions, and MR and BR was defined according to the guidelines for defining hematologic improvement in MDS.
Percent Decrease in Phospho-FLT3 Compared to Baseline (E1) [days 1, 28]
Percent Decrease in Phospho-FLT3 Compared to Baseline (E2) [Days 1, 28]
Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for PKC412 Plasma in the PKC + Itraconazole Combination Arm (E2) [Cycle 1: days 21, 22, 28]
Blood samples were collected for pharmacokinetic (PK) analysis.
Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2) [Cycle 1: days 21, 22, 28]
Blood samples were collected for pharmacokinetic (PK) analysis.
Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2) [Cycle 1: days 21, 22, 28]
Blood samples were collected for PK analysis.
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2) [Cycle 1: days 21, 22, 28]
Blood samples were collected for PK analysis.
Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2) [Cycle 1: days 21 and 22]
Blood samples were collected for PK analysis.
Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for CGP62221 Plasma in the PKC + Itraconazole Combination Arm (E2) [Cycle 1: days 21, 22, 28]
Blood samples were collected for pharmacokinetic (PK) analysis.
Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2) [Cycle 1: days 21, 22, 28]
Blood samples were collected for pharmacokinetic (PK) analysis.
Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2) [Cycle 1: days 21, 22, 28]
Blood samples were collected for PK analysis.
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for CGP622221 in the PKC412 + Itraconazole Combination Arm (E2) [Cycle 1: days 21, 22, 28]
Blood samples were collected for PK analysis.
Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2) [Cycle 1: day 22,]
Blood samples were collected for PK analysis.
Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for CGP52421 Plasma in the PKC + Itraconazole Combination Arm (E2) [Cycle 1: days 21, 22, 28]
Blood samples were collected for pharmacokinetic (PK) analysis.
Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2) [Cycle 1: days 21, 22, 28]
Blood samples were collected for pharmacokinetic (PK) analysis.
Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2) [Cycle 1: days 21, 22, 28]
Blood samples were collected for PK analysis.
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2) [Cycle 1: days 21, 22, 28]
Blood samples were collected for PK analysis.
Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) [Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15]
Blood samples were collected for analysis.
Summary of CGP62221 Concentration (E2) [Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15]
Blood samples were collected for analysis.
Summary of CGP52421 Concentration (E2) [Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15]
Blood samples were collected for analysis.

Secondary Outcome Measures

Time to Disease Progression (TTP) (Core) [from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003]
TTP was defined as the time from first dose date to date of disease progression which is identified as study completion date for unsatisfactory treatment effect or date of death from any cause within the 28 day cutoff post treatment.
Summary of Midostaurin Plasma Concentration (Core) [Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,]
Blood samples were collected for analysis.
Summary of CGP62221 Plasma Concentration (Core) [Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,]
Blood samples were collected for analysis.
Summary of CGP52421 Plasma Concentration (Core) [Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,]
Blood samples were collected for analysis.
Time to Disease Progression (E1) [from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004]
TTP was defined as the time from the first dose date to the date of disease progression (defined as the study completion date for unsatisfactory treatment effect, date of response assessment of progressive disease, or date of death from any cause). One participant from the wild type 200 mg group did not have any assessment on treatment and therefore was not taken into account for TTP.
Overall Survival (OS) (E1) [from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004]
OS was measured from the date of the first dose of treatment to the date of death from any cause or to the last date that the patient was known to be alive (a censored observation).
Duration of Best Clinical Response (E1) [from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004]
Duration of best clinical response was measured from the time that the measurement criteria were met for CR, PR, MR (with or without blast reduction) or BR until the first date that recurrent disease was documented (event) or until the date of last follow up.
Event-free Survival (E1) [from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004]
Event-free survival was defined as the time from date of start of treatment to the date of death from any cause, treatment failure or relapse
Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) [Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h)]
Blood samples were collected for analysis.
Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) [Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h)]
Blood samples were collected for analysis.
Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) [Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h)]
Blood samples were collected for analysis.
Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) [Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h); cycle 5: day 1 (0h) and cycle 6: day 1 (0h)]
Blood samples were collected for analysis.
Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) [Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h); cycle 5: day 1 (0h) and cycle 6: day 1 (0h)]
Blood samples were collected for analysis.
Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) [Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h); cycle 5: day 1 (0h) and cycle 6: day 1 (0h)]
Blood samples were collected for analysis.
Best Clinical Response (E2) [date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008]
Best clinical response was defined as CR, PR, MR, MR+BR, or BR . CR and PR was defined according to NCI definitions, and MR and BR was defined according to the guidelines for defining hematologic improvement in MDS.
Time to Disease Progression (E2) [date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008]
TTP was defined as the time from the first dose date to the date of disease progression, which was defined as the study completion date for unsatisfactory treatment effect, the date of response assessment of progressive disease, or the date of death from any cause
Overall Survival (E2) [date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008]
OS was measured from the date of the first dose of treatment to the date of death from any cause or the last date the patient was known to be alive (censored observation)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Patients:

with AML who are not candidates for myelosuppressive chemotherapy or with AML who have relapsed disease or are refractory to standard therapy and not likely to require cytoreductive therapy within one month or with MDS subtypes refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T) or chronic myelomonocytic leukemia (CMML).

Patients with a relevant FLT3-ITD mutation or D835Y point mutation
Patients at least 18 years or older
Patients with WHO performance status of 0 to 2 with a life expectancy of at least 3 months
Patients must not be treated within 4 weeks after any prior therapy
Written informed consent obtained according to local guidelines

Exclusion criteria:

Patients meeting any of the following criteria during screening will be excluded from entry into the study:

Patients who had prior allogeneic, syngeneic, or autologous bone marrow transplant or stem cell transplant less than 2 months previously.
Female patients who are pregnant or breast feeding, or adults of childbearing age not employing an effective method of birth control.
Concurrent severe and/or uncontrolled medical or psychiatric condition which may interfere with the completion of the study.
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PKC412.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Medical Center	Los Angeles	California	United States	90095
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
3	New York Weill Cornell Medical Center	New York	New York	United States	10021
4	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Novartis Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT00045942

Other Study ID Numbers:

CPKC412A2104
NCT00045578
NCT00977782

First Posted:

Sep 18, 2002

Last Update Posted:

Aug 11, 2017

Last Verified:

Aug 1, 2017

Individual Participant Data (IPD) Sharing Statement:

Undecided

Plan to Share IPD:

Undecided

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Novartis Pharmaceuticals

AML

MDS

high risk myelodysplastic syndrome

Additional relevant MeSH terms:

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Syndrome

Itraconazole

Midostaurin

Study Results

Participant Flow

Recruitment Details	In PKC412A2104 (Core), FLT3 mutated participants with AML or MDS received open-label PKC412. In PKC412A2104E1, FLT3 mutated participants and FLT3 wild type participants were randomized to receive either PKC412 50 mg bid or PKC412 100 mg bid.
Pre-assignment Detail	In PKC412A2104E2, participants were alternately assigned to the regimens, beginning with the first enrolled into the intra-patient dose escalation arm and the next enrolled into the PKC412 + itraconazole arm. Of the 16 participants enrolled in the PKC412 dose escalation arm, 14 were newly enrolled, and 2 were transitioned from PKC412A2104E1.

Arm/Group Title	PKC412 in FLT3 Mutated Participants (Core)	FLT3 Mutated PKC412 100 mg/Day (E1)	FLT3 Mutated PKC412 200 mg/Day (E1)	FLT3 Wild Type PKC412 100 mg/Day (E1)	FLT3 Wild Type PKC412 200 mg/Day (E1)	FLT3 Mutated PKC412 Dose Escalation (E2)	FLT3 Mutated PKC+Itraconazole (E2)	FLT3 Wild Type PKC412 Dose Escalation (E2)	FLT3 Wild Type PKC+Itraconazole (E2)
Arm/Group Description	Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Period Title: PKC412A2104 (Core)
STARTED	20	0	0	0	0	0	0	0	0
Core Primary Efficacy	20	0	0	0	0	0	0	0	0
COMPLETED	0	0	0	0	0	0	0	0	0
NOT COMPLETED	20	0	0	0	0	0	0	0	0
Period Title: PKC412A2104 (Core)
STARTED	0	18	17	33	27	0	0	0	0
Primary Efficacy	0	18	17	32	25	0	0	0	0
COMPLETED	0	0	0	0	0	0	0	0	0
NOT COMPLETED	0	18	17	33	27	0	0	0	0
Period Title: PKC412A2104 (Core)
STARTED	0	0	0	0	0	9	7	7	6
Primary Efficacy	0	0	0	0	0	9	7	7	6
COMPLETED	0	0	0	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	9	7	7	6

Baseline Characteristics

Arm/Group Title	PKC412 in FLT3 Mutated Participants (Core)	FLT3 Mutated PKC412 100 mg/Day (E1)	FLT3 Mutated PKC412 200 mg/Day (E1)	FLT3 Wild Type PKC412 100 mg/Day (E1)	FLT3 Wild Type PKC412 200 mg/Day (E1)	FLT3 Mutated PKC412 Dose Escalation (E2)	FLT3 Mutated PKC+Itraconazole (E2)	FLT3 Wild Type PKC412 Dose Escalation (E2)	FLT3 Wild Type PKC+Itraconazole (E2)	Total
Arm/Group Description	Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.	Total of all reporting groups
Overall Participants	20	18	17	33	27	8	7	6	6	142
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	11 55%	11 61.1%	8 47.1%	7 21.2%	8 29.6%	6 75%	5 71.4%	0 0%	0 0%	56 39.4%
>=65 years	9 45%	7 38.9%	9 52.9%	26 78.8%	19 70.4%	2 25%	2 28.6%	6 100%	6 100%	86 60.6%
Sex: Female, Male (Count of Participants)
Female	6 30%	5 27.8%	9 52.9%	17 51.5%	15 55.6%	3 37.5%	3 42.9%	4 66.7%	4 66.7%	66 46.5%
Male	14 70%	13 72.2%	8 47.1%	16 48.5%	12 44.4%	5 62.5%	4 57.1%	2 33.3%	2 33.3%	76 53.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Best Clinical Response (Core)
Description	Best clinical response was defined as complete response (CR) or partial response (PR), according to NCI definitions for AML and the guidelines for defining responses in MDS.
Time Frame	from date of first patient first visit (FPFV), 29-Jan-2002, to date of last participant last visit (LPLV), 04-Sep-2003

Outcome Measure Data

Analysis Population Description
Core primary efficacy population: The core primary efficacy population included all participants who were randomized.

Arm/Group Title	PKC412 in FLT3 Mutated Participants (Core)
Arm/Group Description	Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	20
Number [Participants]	0 0%

2. Primary Outcome

Title	Percent Decrease in Phospho-FLT3 Compared to Baseline (Core)
Description
Time Frame	days 1, 28

Outcome Measure Data

Analysis Population Description
This outcome measure was not analyzed. Assessment of FLT3 autophosphorylation in leukemic blasts was not possible at the planned time points because the blast reduction was rapid and occurred during the first week in some participants. Thus, by Day 28, the blast count in some participants were too low for autophosphorylation to be measured.

Arm/Group Title	PKC412 in FLT3 Mutated Participants (Core)
Arm/Group Description	Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	0

3. Primary Outcome

Title	Number of Participants With Overall Clinical Response (E1)
Description	Overall clinical response was defined as CR, PR, minor response (MR) or blast response (BR). CR and PR was defined according to NCI definitions, and MR and BR was defined according to the guidelines for defining hematologic improvement in MDS.
Time Frame	from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004

Outcome Measure Data

Analysis Population Description
E1 primary efficacy population: all participants who received at least one dose of study medication, completed at least 8 days of therapy within Cycle 1 unless discontinued due to progressive disease and/or death due to any cause, and who were not considered to be associated with a protocol violation that was exclusionary from the population.

Arm/Group Title	FLT3 Mutated PKC412 100 mg/Day (E1)	FLT3 Mutated PKC412 200 mg/Day (E1)	FLT3 Wild Type PKC412 100 mg/Day (E1)	FLT3 Wild Type PKC412 200 mg/Day (E1)
Arm/Group Description	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	18	17	32	25
Complete response	0 0%	0 0%	0 0%	0 0%
Partial response	0 0%	1 5.6%	0 0%	0 0%
Minor response	1 5%	0 0%	6 35.3%	3 9.1%
Blast response	11 55%	12 66.7%	15 88.2%	8 24.2%
Overall response	12 60%	13 72.2%	21 123.5%	11 33.3%

4. Primary Outcome

Title	Percent Decrease in Phospho-FLT3 Compared to Baseline (E1)
Description
Time Frame	days 1, 28

Outcome Measure Data

Analysis Population Description
The analyses for this outcome measure were not performed due to technical challenges in measuring phosphorylated FLT3 in patient blast samples in an ex vivo setting.

Arm/Group Title	FLT3 Mutated PKC412 100 mg/Day (E1)	FLT3 Mutated PKC412 200 mg/Day (E1)	FLT3 Wild Type PKC412 100 mg/Day (E1)	FLT3 Wild Type PKC412 200 mg/Day (E1)
Arm/Group Description	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	0	0	0	0

5. Primary Outcome

Title	Percent Decrease in Phospho-FLT3 Compared to Baseline (E2)
Description
Time Frame	Days 1, 28

Outcome Measure Data

Analysis Population Description
The analyses for this outcome measure were not performed due to technical challenges in measuring phosphorylated FLT3 in patient blast samples in an ex vivo setting.

Arm/Group Title	FLT3 Mutated PKC412 Dose Escalation (E2)	FLT3 Mutated PKC+Itraconazole (E2)	FLT3 Wild Type PKC412 Dose Escalation (E2)	FLT3 Wild Type PKC+Itraconazole (E2)
Arm/Group Description	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	0	0	0	0

6. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for PKC412 Plasma in the PKC + Itraconazole Combination Arm (E2)
Description	Blood samples were collected for pharmacokinetic (PK) analysis.
Time Frame	Cycle 1: days 21, 22, 28

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	10
Cycle 1, day 21 (n=9)	22261.53 (11984.6)
Cycle 1, day 22 (n=10)	37578.85 (44330.7)
Cycle 1, day 28 (n=7)	35630.45 (23993.2)

7. Primary Outcome

Title	Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2)
Description	Blood samples were collected for pharmacokinetic (PK) analysis.
Time Frame	Cycle 1: days 21, 22, 28

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	10
Cycle 1 , day 21 (n=10)	3945.00 (4440.238)
Cycle 1, day 22 (n=10)	3968.70 (4047.498)
Cycle 1, day 28 (n=8)	3931.25 (2638.135)

8. Primary Outcome

Title	Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2)
Description	Blood samples were collected for PK analysis.
Time Frame	Cycle 1: days 21, 22, 28

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	10
Cycle 1, day 21 (n=10)	1.6
Cycle 1, day 22 (n=10)	1.9
Cycle 1, day 28 (n=8)	2.2

9. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2)
Description	Blood samples were collected for PK analysis.
Time Frame	Cycle 1: days 21, 22, 28

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	10
Cycle 1, day 21 (n=10)	32120.58 (35792.2)
Cycle 1, day 22 (n=10)	34684.6 (37084.9)
Cycle 1, day 28, (n=8)	33020.17 (17206.3)

10. Primary Outcome

Title	Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2)
Description	Blood samples were collected for PK analysis.
Time Frame	Cycle 1: days 21 and 22

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	8
Cycle 1, day 21 (n=6)	18.13 (13.505)
Cycle 1, day 22 (n=8)	13.23 (6.346)

11. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for CGP62221 Plasma in the PKC + Itraconazole Combination Arm (E2)
Description	Blood samples were collected for pharmacokinetic (PK) analysis.
Time Frame	Cycle 1: days 21, 22, 28

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	8
Cycle 1, day 21 (n=8)	30217.82 (16502.90)
Cycle 1, day 22 (n=7)	23824.69 (13300.69)
Cycle 1, day 28 (n=7)	31545.54 (12453.16)

12. Primary Outcome

Title	Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2)
Description	Blood samples were collected for pharmacokinetic (PK) analysis.
Time Frame	Cycle 1: days 21, 22, 28

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	10
Cycle 1, day 21 (n=10)	3259.30 (1747.923)
Cycle 1, day 22 (n=10)	3221.40 (1980.217)
Cycle 1, day 28 (n=8)	3032.25 (1975.371)

13. Primary Outcome

Title	Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2)
Description	Blood samples were collected for PK analysis.
Time Frame	Cycle 1: days 21, 22, 28

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	10
Cycle 1, day 21 (n=10)	3.7
Cycle 1, day 22 (n=10)	2.3
Cycle 1, day 28 (n=8)	3.3

14. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for CGP622221 in the PKC412 + Itraconazole Combination Arm (E2)
Description	Blood samples were collected for PK analysis.
Time Frame	Cycle 1: days 21, 22, 28

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	10
Cycle 1, day 21 (n=10)	31699.93 (15573.87)
Cycle 1, day 22 (n=10)	31182.90 (17380.39)
Cycle 1, day 28 (n=8)	26688.60 (10901.40)

15. Primary Outcome

Title	Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2)
Description	Blood samples were collected for PK analysis.
Time Frame	Cycle 1: day 22,

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For this end point, 4 participants with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	4
Mean (Standard Deviation) [hour]	14.37 (6.743)

16. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for CGP52421 Plasma in the PKC + Itraconazole Combination Arm (E2)
Description	Blood samples were collected for pharmacokinetic (PK) analysis.
Time Frame	Cycle 1: days 21, 22, 28

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	9
Cycle 1, day 21 (n=9)	40258.65 (9747.374)
Cycle 1, day 22 (n=7)	42950.76 (8604.972)
Cycle 1, day 28 (n=7)	49758.77 (7733.621)

17. Primary Outcome

Title	Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2)
Description	Blood samples were collected for pharmacokinetic (PK) analysis.
Time Frame	Cycle 1: days 21, 22, 28

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	10
Cycle 1, day 21 (n=10)	4173.00 (985.473)
Cycle 1, day 22 (n=10)	4293.00 (1292.380)
Cycle 1, day 28 (n=8)	4875.00 (1376.382)

18. Primary Outcome

Title	Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2)
Description	Blood samples were collected for PK analysis.
Time Frame	Cycle 1: days 21, 22, 28

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	10
Cycle 1, day 21 (n=10)	3.5
Cycle 1, day 22 (n=10)	2.1
Cycle 1, day 28 (n=8)	2.2

19. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2)
Description	Blood samples were collected for PK analysis.
Time Frame	Cycle 1: days 21, 22, 28

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population in the midostaurin + itraconazole FLT3 mutated and FLT3 wild-type combined arms, which consisted of 10 participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and FLT3 Wild Type PKC + Itraconazole Combined
Arm/Group Description	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	10
Cycle 1, day 21 (n=10)	38899.84 (7616.481)
Cycle 1, day 22 (n=10)	41035.50 (10807.22)
Cycle 1, day 28 (n=8)	44447.05 (8906.006)

20. Primary Outcome

Title	Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2)
Description	Blood samples were collected for analysis.
Time Frame	Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15

Outcome Measure Data

Analysis Population Description
The PK analysis set of the FLT3 mutated PKC412 dose escalation and FLT3 wild type PKC412 dose escalation combined arms, which consisted of the 14 newly enrolled participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and Wild Type PKC412 Dose Escalation Combined
Arm/Group Description	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.
Measure Participants	12
Cycle 1, day 1 (=7)	0
Cycle 1, day 2 (24 hours post day 1) (n=12)	2565.0
Cycle 1, day 3 (n=12)	3100.0
Cycle 1, day 8 (n=8)	1640.0
Cycle 1, day 15 (n=6)	744.5
Cycle 1, day 16 (24 hr post day 15) (n=6)	836.0
Cycle 1, day 17 (n=5)	800.0
Cycle 1, day 22 (n=5)	1410.0
Cycle 2, day 1 (n=4)	772.0
Cycle 2, day 2 (24 hr post day 1) (n=4)	1141.0
Cycle 2, day3 (n=4)	1295.0
Cycle 2, day 8 (n=4)	1210.0
Cycle 2, day 15 (n=3)	834.0

21. Primary Outcome

Title	Summary of CGP62221 Concentration (E2)
Description	Blood samples were collected for analysis.
Time Frame	Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15

Outcome Measure Data

Analysis Population Description
The PK analysis set of the FLT3 mutated PKC412 dose escalation and FLT3 wild type PKC412 dose escalation combined arms, which consisted of the 14 newly enrolled participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and Wild Type PKC412 Dose Escalation Combined
Arm/Group Description	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.
Measure Participants	12
Cycle 1, day 1 (n=7)	0
Cycle 1, day 2 (24 hr post day 1) (n=12)	1320.0
Cycle 1, day 3 (n=12)	2750.0
Cycle 1, day 8 (n=8)	2380.0
Cycle 1, day 15 (n=6)	1505.0
Cycle 1, day 16 (24 hr post day 15) (n=6)	1425.0
Cycle 1, day 17 (n=5)	1480.0
Cycle 1, day 22 (n=5)	1520.0
Cycle 2, day 1 (n=4)	1545.0
Cycle 2, day 2 (24 hr post day 1) (n=4)	1945.0
Cycle 2, day 3 (n=4)	2070.0
Cycle 2, day 8 (n=4)	2030.0
Cycle 2, day 15 (n=3)	1740.0

22. Primary Outcome

Title	Summary of CGP52421 Concentration (E2)
Description	Blood samples were collected for analysis.
Time Frame	Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15

Outcome Measure Data

Analysis Population Description
The PK analysis set of the FLT3 mutated PKC412 dose escalation and FLT3 wild type PKC412 dose escalation combined arms, which consisted of the 14 newly enrolled participants, was considered for the analysis. For each time point, participants of the PK analysis set with non-missing values were analyzed.

Arm/Group Title	FLT3 Mutated and Wild Type PKC412 Dose Escalation Combined
Arm/Group Description	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.
Measure Participants	12
Cycle 1, day 1 (n=7)	0
Cycle 1, day 2 (24 hr post day 1) (n=12)	684.0
Cycle 1, day 3 (n=12)	1185.0
Cycle 1, day 8 (n=8)	2835.0
Cycle 1, day 15 (n=6)	3845.0
Cycle 1, day 16 (24 hr post day 15) (n=6)	3830.0
Cycle 1, day 17 (n=5)	3620.0
Cycle 1, day 22 (n=5)	4470.0
Cycle 2, day 1 (n=4)	4915.0
Cycle 2, day 2 (24 hr post day 1) (n=4)	4455.0
Cycle 2, day 3 (n=4)	4470.0
Cycle 2, day 8 (n=4)	4860.0
Cycle 2, day 15 (n=3)	4030.0

23. Secondary Outcome

Title	Time to Disease Progression (TTP) (Core)
Description	TTP was defined as the time from first dose date to date of disease progression which is identified as study completion date for unsatisfactory treatment effect or date of death from any cause within the 28 day cutoff post treatment.
Time Frame	from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003

Outcome Measure Data

Analysis Population Description
Core primary efficacy population: The core primary efficacy population included all participants who were randomized.

Arm/Group Title	PKC412 in FLT3 Mutated Participants (Core)
Arm/Group Description	Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	20
Median (95% Confidence Interval) [days]	63.0

24. Secondary Outcome

Title	Summary of Midostaurin Plasma Concentration (Core)
Description	Blood samples were collected for analysis.
Time Frame	Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,

Outcome Measure Data

Analysis Population Description
The Core PK analysis set, which consisted of 15 participants, was considered for the analysis. For each time point, only participants of the PK set who had non-missing values were analyzed.

Arm/Group Title	PKC412 in FLT3 Mutated Participants (Core)
Arm/Group Description	Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	10
Cycle 1, day 1(24 hour) (n=10)	3801.0 (2529.069)
Cycle 1, day 3 (n=7)	7152.86 (4254.173)
Cycle 1, day 8 (n=9)	5154.44 (5004.511)
Cycle 2, day 1 (n=6)	1873.17 (1521.685)

25. Secondary Outcome

Title	Summary of CGP62221 Plasma Concentration (Core)
Description	Blood samples were collected for analysis.
Time Frame	Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,

Outcome Measure Data

Analysis Population Description
The Core PK analysis set, which consisted of 15 participants, were considered for the analysis. For each time point, only participants of the PK set who had non-missing values were analyzed.

Arm/Group Title	PKC412 in FLT3 Mutated Participants (Core)
Arm/Group Description	Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	10
Cycle 1, day 1 (24 hour) (n=10)	1636.00 (612.938)
Cycle 1, day 3 (n=7)	3143.71 (1147.407)
Cycle 1, day 8 (n=9)	4873.33 (3421.593)
Cycle 2, day 1 (n=6)	2816.67 (2095.850)

26. Secondary Outcome

Title	Summary of CGP52421 Plasma Concentration (Core)
Description	Blood samples were collected for analysis.
Time Frame	Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,

Outcome Measure Data

Analysis Population Description
The Core PK analysis set, which consisted of 15 participants, were considered for the analysis. For each time point, only participants of the PK set who had non-missing values were analyzed.

Arm/Group Title	PKC412 in FLT3 Mutated Participants (Core)
Arm/Group Description	Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	10
Cycle 1, day 1 (24 hour) (n=10)	951.70 (297.866)
Cycle 1, day 3 (n=7)	1846.57 (657.472)
Cycle 1, day 8 (n=9)	6342.22 (2586.440)
Cycle 2, day 1 (n=6)	12978.33 (4036.436)

27. Secondary Outcome

Title	Time to Disease Progression (E1)
Description	TTP was defined as the time from the first dose date to the date of disease progression (defined as the study completion date for unsatisfactory treatment effect, date of response assessment of progressive disease, or date of death from any cause). One participant from the wild type 200 mg group did not have any assessment on treatment and therefore was not taken into account for TTP.
Time Frame	from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004

Outcome Measure Data

Analysis Population Description
Primary efficacy population: defined as all patients who received at least 1 dose of study medication, completed at least eight days of therapy within Cycle 1 unless discontinued due to progressive disease and/or death due to any cause, and who were not considered to be associated with a protocol violation that was exclusionary from the population.

Arm/Group Title	FLT3 Mutated PKC412 100 mg/Day (E1)	FLT3 Mutated PKC412 200 mg/Day (E1)	FLT3 Wild Type PKC412 100 mg/Day (E1)	FLT3 Wild Type PKC412 200 mg/Day (E1)
Arm/Group Description	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	18	17	32	25
Median (95% Confidence Interval) [days]	77.0	50.0	62.0	54.0

28. Secondary Outcome

Title	Overall Survival (OS) (E1)
Description	OS was measured from the date of the first dose of treatment to the date of death from any cause or to the last date that the patient was known to be alive (a censored observation).
Time Frame	from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004

Outcome Measure Data

Analysis Population Description
Primary efficacy population: defined as all patients who received at least 1 dose of study medication, completed at least eight days of therapy within Cycle 1 unless discontinued due to progressive disease and/or death due to any cause, and who were not considered to be associated with a protocol violation that was exclusionary from the population.

Arm/Group Title	FLT3 Mutated PKC412 100 mg/Day (E1)	FLT3 Mutated PKC412 200 mg/Day (E1)	FLT3 Wild Type PKC412 100 mg/Day (E1)	FLT3 Wild Type PKC412 200 mg/Day (E1)
Arm/Group Description	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	18	17	32	25
Median (95% Confidence Interval) [days]	99.0	93.0	145.0	159.0

29. Secondary Outcome

Title	Duration of Best Clinical Response (E1)
Description	Duration of best clinical response was measured from the time that the measurement criteria were met for CR, PR, MR (with or without blast reduction) or BR until the first date that recurrent disease was documented (event) or until the date of last follow up.
Time Frame	from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004

Outcome Measure Data

Analysis Population Description
Responders from the PEP; PEP defined as all patients who received at least 1 dose of study medication, completed at least 8 days of therapy within Cycle 1 unless discontinued due to progressive disease and/or death due to any cause, and who were not considered to be associated with a protocol violation that was exclusionary from the population.

Arm/Group Title	FLT3 Mutated PKC412 100 mg/Day (E1)	FLT3 Mutated PKC412 200 mg/Day (E1)	FLT3 Wild Type PKC412 100 mg/Day (E1)	FLT3 Wild Type PKC412 200 mg/Day (E1)
Arm/Group Description	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	12	13	21	11
Median (95% Confidence Interval) [days]	57.0	29.0	56.0	58.0

30. Secondary Outcome

Title	Event-free Survival (E1)
Description	Event-free survival was defined as the time from date of start of treatment to the date of death from any cause, treatment failure or relapse
Time Frame	from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004

Outcome Measure Data

Analysis Population Description
Primary efficacy population: defined as all patients who received at least 1 dose of study medication, completed at least eight days of therapy within Cycle 1 unless discontinued due to progressive disease and/or death due to any cause, and who were not considered to be associated with a protocol violation that was exclusionary from the population.

Arm/Group Title	FLT3 Mutated PKC412 100 mg/Day (E1)	FLT3 Mutated PKC412 200 mg/Day (E1)	FLT3 Wild Type PKC412 100 mg/Day (E1)	FLT3 Wild Type PKC412 200 mg/Day (E1)
Arm/Group Description	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	18	17	32	25
Median (95% Confidence Interval) [days]	60.0	50.0	58.0	1.0

31. Secondary Outcome

Title	Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1)
Description	Blood samples were collected for analysis.
Time Frame	Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h)

Outcome Measure Data

Analysis Population Description
The PK population of the mutated PKC412 100 mg/day and wild type PKC412 100 mg/day arms combined, which consisted of all participants who provided at least one evaluable PK sample and received at least one dose of study treatment, was considered for the analysis. For each time point, only participants with non-missing values were analyzed..

Arm/Group Title	FLT3 Mutated and Wild Type PKC412 100 mg/Day Arms Combined
Arm/Group Description	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	43
Cycle 1, day 1 (0h) (n=43)	0.000 (0.0000)
Cycle 1, day 1 (4h) (n=38)	1198.000 (522.4766)
Cycle 1, day 1 (24h) (n=39)	1735.974 (1161.933)
Cycle 1, day 3 (0h) (n=34)	2585.471 (1843.852)
Cycle 1, day 8 (0h) (n=30)	3576.467 (3263.112)
Cycle 2, day 1 (0h) (n=22)	1756.500 (1695.327)
Cycle 3, day 1 (0h) (n=12)	2038.417 (2079.252)
Cycle 4, day 1 (0h) (n=4)	820.750 (565.0247)

32. Secondary Outcome

Title	Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1)
Description	Blood samples were collected for analysis.
Time Frame	Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h)

Outcome Measure Data

Analysis Population Description
The PK population of the mutated PKC412 100 mg/day and wild type PKC412 100 mg/day arms combined, which consisted of all participants who provided at least one evaluable PK sample and received at least one dose of study treatment, was considered for the analysis. For each time point, only participants with non-missing values were analyzed..

Arm/Group Title	FLT3 Mutated and Wild Type PKC412 100 mg/Day Arms Combined
Arm/Group Description	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	44
Cycle 1, day 1 (0h) (n=44)	0.000 (0.0000)
Cycle 1, day 1 (4h) (n=38)	367.079 (220.2728)
Cycle 1, day 1 (24h) (n=39)	808.182 (375.4818)
Cycle 1, day 3 (0h) (n=34)	1400.476 (681.9106)
Cycle 1, day 8 (0h) (n=30)	2868.933 (1723.985)
Cycle 2, day 1 (0h) (n=22)	1930.000 (1241.980)
Cycle 3, day 1 (0h) (n=12)	1971.500 (1519.628)
Cycle 4, day 1 (0h) (n=4)	1207.500 (310.5238)

33. Secondary Outcome

Title	Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1)
Description	Blood samples were collected for analysis.
Time Frame	Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h)

Outcome Measure Data

Analysis Population Description
The PK population of the mutated PKC412 100 mg/day and wild type PKC412 100 mg/day arms combined, which consisted of all participants who provided at least one evaluable PK sample and received at least one dose of study treatment, was considered for the analysis. For each time point, only participants with non-missing values were analyzed..

Arm/Group Title	FLT3 Mutated and Wild Type PKC412 100 mg/Day Arms Combined
Arm/Group Description	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	41
Cycle 1, day 1 (0h) (n=41)	0.000 (0.0000)
Cycle 1, day 1 (4h) (n=38)	203.013 (121.3817)
Cycle 1, day 1 (24h) (n=39)	436.282 (210.1306)
Day 1, day 3 (0h) (n=34)	1188.359 (1833.644)
Cycle 1, day 8 (0h) (n=30)	2840.833 (1158.132)
Cycle 2, day 1 (0h) (n=22)	6467.591 (3434.776)
Cycle 3, day 1 (0h) (n=12)	8175.000 (4851.968)
Cycle 4, day 1 (0h) (n=4)	6205.000 (1619.084)

34. Secondary Outcome

Title	Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1)
Description	Blood samples were collected for analysis.
Time Frame	Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h); cycle 5: day 1 (0h) and cycle 6: day 1 (0h)

Outcome Measure Data

Analysis Population Description
The PK population of the mutated PKC412 200 mg/day and wild type PKC412 200 mg/day arms combined, which consisted of all participants who provided at least one evaluable PK sample and received at least one dose of study treatment, was considered for the analysis. For each time point, only participants with non-missing values were analyzed..

Arm/Group Title	FLT3 Mutated and Wild Type PKC412 200 mg/Day
Arm/Group Description	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	38
Cycle 1, day 1 (0h) (n=38)	0.000 (0.0000)
Cycle 1, day 1 (4h) (n=34)	2087.088 (1087.277)
Cycle 1, day 1 (24h) (n=36)	2849.731 (2150.176)
Cycle 1, day 3 (0h) (n=29)	3756.483 (2549.759)
Cycle 1, day 8 (0h) (n=24)	4447.583 (4233.285)
Cycle 2, day 1 (0h) (n=15)	1226.333 (894.1562)
Cycle 3, day 2 (0h) (n=6)	754.500 (264.6860)
Cycle 4, day 1 (0h) (n=6)	1187.167 (1026.004)
Cycle 5, day 1 (0h) (n=4)	572.250 (314.7405)
Cycle 6, day 1 (0h) (n=4)	1433.250 (1670.029)

35. Secondary Outcome

Title	Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1)
Description	Blood samples were collected for analysis.
Time Frame	Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h); cycle 5: day 1 (0h) and cycle 6: day 1 (0h)

Outcome Measure Data

Analysis Population Description
The PK population of the mutated PKC412 200 mg/day and wild type PKC412 200 mg/day arms combined, which consisted of all participants who provided at least one evaluable PK sample and received at least one dose of study treatment, was considered for the analysis. For each time point, only participants with non-missing values were analyzed..

Arm/Group Title	FLT3 Mutated and Wild Type PKC412 200 mg/Day
Arm/Group Description	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	39
Cycle 1, day 1 (0h) (n=39)	0.000 (0.0000)
Cycle 1, day 1 (4h) (n=34)	471.635 (342.7850)
Cycle 1, day 1 (24h) (n=36)	1134.764 (655.1779)
Cycle 1, day 3 (0h) (n=29)	1944.069 (1049.770)
Cycle 1, day 8 (0h) (n=24)	2898.708 (1876.446)
Cycle 2, day 1 (0h) (n=15)	1828.667 (650.1524)
Cycle 3, day 2 (0h) (n=6)	1258.333 (289.0271)
Cycle 4, day 1 (0h) (n=6)	1602.950 (1071.167)
Cycle 5, day 1 (0h) (n4)	1111.250 (357.8728)
Cycle 6, day 1 (0h) (n=4)	1662.500 (864.4603)

36. Secondary Outcome

Title	Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1)
Description	Blood samples were collected for analysis.
Time Frame	Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h); cycle 5: day 1 (0h) and cycle 6: day 1 (0h)

Outcome Measure Data

Analysis Population Description
The PK population of the mutated PKC412 200 mg/day and wild type PKC412 200 mg/day arms combined, which consisted of all participants who provided at least one evaluable PK sample and received at least one dose of study treatment, was considered for the analysis. For each time point, only participants with non-missing values were analyzed..

Arm/Group Title	FLT3 Mutated and Wild Type PKC412 200 mg/Day
Arm/Group Description	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Measure Participants	38
Cycle 1, day 1 (0h) (n=38)	0.000 (0.0000)
Cycle 1, day 1 (4h) (n=34)	257.391 (148.6420)
Cycle 1, day 1 (24h) (n=36)	666.194 (313.5770)
Cycle 1, day 3 (0h) (n=29)	1394.062 (653.2943)
Cycle 1, day 8 (0h) (n=24)	4447.500 (1359.192)
Cycle 2, day 1 (0h) (n=15)	9196.667 (3248.590)
Cycle 3, day 2 (0h) (n=6)	8811.667 (3376.172)
Cycle 4, day 1 (0h) (n=6)	6266.667 (3895.452)
Cycle 5, day 1 (0h) (n4)	7845.000 (4078.313)
Cycle 6, day 1 (0h) (n=4)	8710.000 (4890.774)

37. Secondary Outcome

Title	Best Clinical Response (E2)
Description	Best clinical response was defined as CR, PR, MR, MR+BR, or BR . CR and PR was defined according to NCI definitions, and MR and BR was defined according to the guidelines for defining hematologic improvement in MDS.
Time Frame	date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008

Outcome Measure Data

Analysis Population Description
The primary efficacy population, which included all participants, who received at least one dose of study drug and who completed at least 8 days of treatment in Cycle 1, unless they discontinued due to progressive disease and/or death due to any cause, and who did not experience any protocol violations, was analyzed..

Arm/Group Title	FLT3 Mutated PKC412 Dose Escalation (E2)	FLT3 Mutated PKC+Itraconazole (E2)	FLT3 Wild Type PKC412 Dose Escalation (E2)	FLT3 Wild Type PKC+Itraconazole (E2)
Arm/Group Description	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	9	7	7	6
Complete response	0 0%	0 0%	0 0%	1 3%
Partial response	0 0%	0 0%	0 0%	0 0%
Minor response	0 0%	0 0%	0 0%	1 3%
Minor response and blast response	1 5%	0 0%	2 11.8%	1 3%
Blast response	4 20%	0 0%	0 0%	1 3%
Best clinical response	5 25%	0 0%	2 11.8%	4 12.1%

38. Secondary Outcome

Title	Time to Disease Progression (E2)
Description	TTP was defined as the time from the first dose date to the date of disease progression, which was defined as the study completion date for unsatisfactory treatment effect, the date of response assessment of progressive disease, or the date of death from any cause
Time Frame	date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008

Outcome Measure Data

Analysis Population Description
The primary efficacy population, which included all participants, who received at least one dose of study drug and who completed at least 8 days of treatment in Cycle 1, unless they discontinued due to progressive disease and/or death due to any cause, and who did not experience any protocol violations, was analyzed..

Arm/Group Title	FLT3 Mutated PKC412 Dose Escalation (E2)	FLT3 Mutated PKC+Itraconazole (E2)	FLT3 Wild Type PKC412 Dose Escalation (E2)	FLT3 Wild Type PKC+Itraconazole (E2)
Arm/Group Description	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	9	7	7	6
Median (95% Confidence Interval) [days]	49.0	26.0	169.0	78.0

39. Secondary Outcome

Title	Overall Survival (E2)
Description	OS was measured from the date of the first dose of treatment to the date of death from any cause or the last date the patient was known to be alive (censored observation)
Time Frame	date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008

Outcome Measure Data

Analysis Population Description
The primary efficacy population, which included all participants, who received at least one dose of study drug and who completed at least 8 days of treatment in Cycle 1, unless they discontinued due to progressive disease and/or death due to any cause, and who did not experience any protocol violations, was analyzed..

Arm/Group Title	FLT3 Mutated PKC412 Dose Escalation (E2)	FLT3 Mutated PKC+Itraconazole (E2)	FLT3 Wild Type PKC412 Dose Escalation (E2)	FLT3 Wild Type PKC+Itraconazole (E2)
Arm/Group Description	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.	Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.	Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Measure Participants	9	7	7	6
Median (95% Confidence Interval) [days]	116.0	75.0	372.0	220.0

Adverse Events

	PKC412 Core		FLT3 Mutated PKC412 100 mg/Day (E1)		FLT3 Mutated PKC412 200 mg/Day (E1)		FLT3 Wild Type PKC412 100 mg/Day (E1)		FLT3 Wild Type PKC412 200 mg/Day (E1)		FLT3 Mutated PKC412 Dose Escalation (E2)		FLT3 Mutated PKC+Itraconazole (E2)		FLT3 Wild Type PKC412 Dose Escalation (E2)		FLT3 Wild Type PKC+Itraconazole (E2)
Time Frame
Adverse Event Reporting Description

Arm/Group Title	PKC412 Core		FLT3 Mutated PKC412 100 mg/Day (E1)		FLT3 Mutated PKC412 200 mg/Day (E1)		FLT3 Wild Type PKC412 100 mg/Day (E1)		FLT3 Wild Type PKC412 200 mg/Day (E1)		FLT3 Mutated PKC412 Dose Escalation (E2)		FLT3 Mutated PKC+Itraconazole (E2)		FLT3 Wild Type PKC412 Dose Escalation (E2)		FLT3 Wild Type PKC+Itraconazole (E2)
Arm/Group Description	Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.		Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.		Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.		Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.		Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.		Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.		Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.		Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.		Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
All Cause Mortality
	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	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	PKC412 Core		FLT3 Mutated PKC412 100 mg/Day (E1)		FLT3 Mutated PKC412 200 mg/Day (E1)		FLT3 Wild Type PKC412 100 mg/Day (E1)		FLT3 Wild Type PKC412 200 mg/Day (E1)		FLT3 Mutated PKC412 Dose Escalation (E2)		FLT3 Mutated PKC+Itraconazole (E2)		FLT3 Wild Type PKC412 Dose Escalation (E2)		FLT3 Wild Type PKC+Itraconazole (E2)
	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	12/20 (60%)		16/18 (88.9%)		14/17 (82.4%)		22/33 (66.7%)		19/27 (70.4%)		7/9 (77.8%)		6/7 (85.7%)		5/7 (71.4%)		3/6 (50%)
Blood and lymphatic system disorders
Anaemia	0/20 (0%)		0/18 (0%)		0/17 (0%)		3/33 (9.1%)		3/27 (11.1%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Anaemia NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Anaemia haemolytic autoimmune	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Disseminated intravascular coagulation	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Febrile neutropenia	3/20 (15%)		3/18 (16.7%)		3/17 (17.6%)		9/33 (27.3%)		5/27 (18.5%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		2/6 (33.3%)
Leukocytosis	2/20 (10%)		1/18 (5.6%)		1/17 (5.9%)		1/33 (3%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Neutropenia	1/20 (5%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pancytopenia	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Splenic infarction	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Splenomegaly	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		1/9 (11.1%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Thrombocytopenia	1/20 (5%)		0/18 (0%)		1/17 (5.9%)		3/33 (9.1%)		3/27 (11.1%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cardiac disorders
Acute coronary syndrome	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Angina pectoris	0/20 (0%)		0/18 (0%)		0/17 (0%)		2/33 (6.1%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		1/6 (16.7%)
Angina unstable	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Aortic valve incompetence	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Atrial fibrillation	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Atrioventricular block	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cardiac aneurysm	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Cardiac arrest	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cardiac failure	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cardiac failure acute	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Cardiac failure congestive	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Cardiomegaly	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cardiopulmonary failure	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Myocardial infarction	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		2/33 (6.1%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Pericardial effusion	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		2/9 (22.2%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Sinus tachycardia	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Tachycardia	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Congenital, familial and genetic disorders
Aplasia	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Ear and labyrinth disorders
Vertigo	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Eye disorders
Blindness	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Erythema of eyelid	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gastrointestinal disorders
Abdominal pain	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Abdominal pain NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Abdominal pain upper	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Constipation	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Diarrhoea	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Gastric polyps	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gastrointestinal haemorrhage	0/20 (0%)		0/18 (0%)		0/17 (0%)		2/33 (6.1%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Intestinal prolapse	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Melaena	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Nausea	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Oral pain	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pancreatitis	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pneumatosis intestinalis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Polyp colorectal	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Proctalgia	0/20 (0%)		0/18 (0%)		2/17 (11.8%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Vomiting	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
General disorders
Asthenia	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Chest discomfort	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Chest pain	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Chills	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Disease progression	0/20 (0%)		2/18 (11.1%)		1/17 (5.9%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Drug interaction	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Fatigue	0/20 (0%)		0/18 (0%)		0/17 (0%)		2/33 (6.1%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
General physical health deterioration	0/20 (0%)		1/18 (5.6%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		1/6 (16.7%)
Injection site cellulitis	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Lethargy	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Mucosal inflammation	0/20 (0%)		1/18 (5.6%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Multi-organ failure	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Performance status decreased	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pyrexia	2/20 (10%)		1/18 (5.6%)		1/17 (5.9%)		5/33 (15.2%)		6/27 (22.2%)		4/9 (44.4%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Hepatobiliary disorders
Cholelithiasis	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gallbladder disorder	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hepatic failure	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hepatocellular damage	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hepatomegaly	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hyperbilirubinaemia	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Liver disorder	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Infections and infestations
Acute sinusitis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Arthritis infective	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Aspergillosis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Bacterial sepsis	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Bronchopneumonia	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Bronchopneumonia NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Candida sepsis	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Candidiasis	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Catheter bacteraemia	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cellulitis	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Central line infection	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Enterococcal bacteraemia	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Enterococcal sepsis	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Erysipelas	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gangrene	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gastroenteritis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Gastrointestinal infection	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Infection	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Lobar pneumonia	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Mastoiditis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Mycobacterium avium complex infection	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Neutropenic infection	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Osteomyelitis	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Perianal abscess	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pharyngitis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pneumonia	0/20 (0%)		5/18 (27.8%)		1/17 (5.9%)		9/33 (27.3%)		3/27 (11.1%)		1/9 (11.1%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Pneumonia NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pneumonia fungal	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pneumonia klebsiella	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pseudomonal sepsis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Respiratory tract infection NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Sepsis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		4/27 (14.8%)		1/9 (11.1%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Sepsis NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Septic shock	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Sinusitis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Sinusitis NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Skin infection	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Soft tissue infection NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Staphylococcal infection	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Thrombophlebitis septic	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Viral upper respiratory tract infection	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Injury, poisoning and procedural complications
Contusion	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Fall	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Subdural haematoma	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Subdural haemorrhage	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Transfusion reaction	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Investigations
Alanine aminotransferase increased	0/20 (0%)		0/18 (0%)		2/17 (11.8%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Aspartate aminotransferase increased	0/20 (0%)		0/18 (0%)		2/17 (11.8%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Bacteria stool identified	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Blast cell count increased	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		2/7 (28.6%)		1/7 (14.3%)		0/6 (0%)
Blood amylase increased	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Blood bilirubin increased	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Blood creatinine increased	0/20 (0%)		0/18 (0%)		0/17 (0%)		2/33 (6.1%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Blood pressure increased	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Breath sounds abnormal	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
C-reactive protein increased	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Culture urine positive	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Fibrinolysis increased	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Gram stain positive	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Lipase increased	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Platelet count increased	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Transaminases increased	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Troponin NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Urine output decreased	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
White blood cell count decreased	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
White blood cell count increased	0/20 (0%)		0/18 (0%)		0/17 (0%)		2/33 (6.1%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Metabolism and nutrition disorders
Anorexia	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cachexia	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Decreased appetite	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Dehydration	1/20 (5%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Diabetes mellitus	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Diabetes mellitus non-insulin-dependent	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Failure to thrive	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Fluid retention	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gout	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hyperglycaemia	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hypokalaemia	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Hyponatraemia	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Lactic acidosis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Arthritis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Back pain	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Bone infarction	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Chondrocalcinosis pyrophosphate	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Coccydynia	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Joint effusion	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Joint stiffness	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Neck pain	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Osteonecrosis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pain in extremity	1/20 (5%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Blast cell crisis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Leukaemia recurrent	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Leukaemic infiltration pulmonary	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Leukostasis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Malignant neoplasm progression	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Tumour lysis syndrome	1/20 (5%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Nervous system disorders
Aphasia	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Asterixis	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cerebral haemorrhage	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cerebral infarction	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cerebrovascular accident	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Coma	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Dizziness	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Dysarthria	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Facial palsy	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Haemorrhage intracranial	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Headache	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hemiparesis	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Metabolic encephalopathy NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Nervous system disorder	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Neurological symptom	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Somnolence	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Syncope	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Tonic clonic movements	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Psychiatric disorders
Confusional state	1/20 (5%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Delirium	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Renal and urinary disorders
Hydronephrosis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Renal failure	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Renal failure acute	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Reproductive system and breast disorders
Bartholin's cyst	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Breast pain	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Respiratory, thoracic and mediastinal disorders
Cough	1/20 (5%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Dyspnoea	1/20 (5%)		2/18 (11.1%)		2/17 (11.8%)		2/33 (6.1%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Haemoptysis	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hypoxia	4/20 (20%)		0/18 (0%)		2/17 (11.8%)		2/33 (6.1%)		1/27 (3.7%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Lung infiltration	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Maxillary sinusitis	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pharyngolaryngeal pain	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pleural effusion	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		2/27 (7.4%)		1/9 (11.1%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Productive cough	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pulmonary alveolar haemorrhage	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pulmonary congestion	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pulmonary embolism	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pulmonary hypertension	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pulmonary oedema	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		2/33 (6.1%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pulmonary oedema NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Respiratory arrest	1/20 (5%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Respiratory distress	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Respiratory failure	1/20 (5%)		1/18 (5.6%)		1/17 (5.9%)		1/33 (3%)		2/27 (7.4%)		1/9 (11.1%)		2/7 (28.6%)		0/7 (0%)		0/6 (0%)
Wheezing	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Skin and subcutaneous tissue disorders
Dermatitis	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hyperhidrosis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Rash	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Rash maculo-papular	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Septal panniculitis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Skin lesion	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Urticaria NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Vascular disorders
Deep vein thrombosis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Haemorrhage	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Hypotension	0/20 (0%)		2/18 (11.1%)		0/17 (0%)		0/33 (0%)		3/27 (11.1%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hypotension NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Orthostatic hypotension	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Venous stasis	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	PKC412 Core		FLT3 Mutated PKC412 100 mg/Day (E1)		FLT3 Mutated PKC412 200 mg/Day (E1)		FLT3 Wild Type PKC412 100 mg/Day (E1)		FLT3 Wild Type PKC412 200 mg/Day (E1)		FLT3 Mutated PKC412 Dose Escalation (E2)		FLT3 Mutated PKC+Itraconazole (E2)		FLT3 Wild Type PKC412 Dose Escalation (E2)		FLT3 Wild Type PKC+Itraconazole (E2)
	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	20/20 (100%)		17/18 (94.4%)		16/17 (94.1%)		32/33 (97%)		27/27 (100%)		9/9 (100%)		6/7 (85.7%)		7/7 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Anaemia	0/20 (0%)		3/18 (16.7%)		1/17 (5.9%)		7/33 (21.2%)		3/27 (11.1%)		3/9 (33.3%)		0/7 (0%)		4/7 (57.1%)		4/6 (66.7%)
Anaemia NOS	4/20 (20%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Coagulopathy	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		3/33 (9.1%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Febrile neutropenia	1/20 (5%)		2/18 (11.1%)		1/17 (5.9%)		0/33 (0%)		3/27 (11.1%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		1/6 (16.7%)
Leukocytosis	2/20 (10%)		1/18 (5.6%)		1/17 (5.9%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Leukopenia	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		2/9 (22.2%)		0/7 (0%)		1/7 (14.3%)		2/6 (33.3%)
Lymph node pain	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Lymphadenopathy	3/20 (15%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Neutropenia	1/20 (5%)		5/18 (27.8%)		0/17 (0%)		4/33 (12.1%)		1/27 (3.7%)		2/9 (22.2%)		0/7 (0%)		2/7 (28.6%)		2/6 (33.3%)
Pancytopenia	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Splenomegaly	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Thrombocythaemia	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Thrombocytopenia	2/20 (10%)		5/18 (27.8%)		1/17 (5.9%)		4/33 (12.1%)		4/27 (14.8%)		0/9 (0%)		1/7 (14.3%)		1/7 (14.3%)		2/6 (33.3%)
Cardiac disorders
Atrial fibrillation	1/20 (5%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Bradycardia	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Bradycardia NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cardiac failure congestive	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cardiovascular disorder	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Mitral valve incompetence	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Pericardial effusion	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Sinus tachycardia	1/20 (5%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Tachycardia	0/20 (0%)		2/18 (11.1%)		2/17 (11.8%)		0/33 (0%)		1/27 (3.7%)		3/9 (33.3%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Tachycardia NOS	3/20 (15%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Ear and labyrinth disorders
Deafness neurosensory	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hypoacusis	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Mastoid disorder	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Vertigo	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Endocrine disorders
Hyperaldosteronism	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Hyperthyroidism	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Eye disorders
Eye swelling	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Eyelid oedema	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Gastrointestinal disorders
Abdominal distension	2/20 (10%)		2/18 (11.1%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Abdominal pain	0/20 (0%)		4/18 (22.2%)		2/17 (11.8%)		0/33 (0%)		6/27 (22.2%)		3/9 (33.3%)		0/7 (0%)		3/7 (42.9%)		1/6 (16.7%)
Abdominal pain NOS	3/20 (15%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Abdominal pain lower	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Abdominal pain upper	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Anal fissure	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Aphthous stomatitis	0/20 (0%)		2/18 (11.1%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Constipation	3/20 (15%)		1/18 (5.6%)		5/17 (29.4%)		3/33 (9.1%)		8/27 (29.6%)		1/9 (11.1%)		2/7 (28.6%)		3/7 (42.9%)		2/6 (33.3%)
Diarrhoea	0/20 (0%)		5/18 (27.8%)		8/17 (47.1%)		12/33 (36.4%)		15/27 (55.6%)		5/9 (55.6%)		3/7 (42.9%)		4/7 (57.1%)		3/6 (50%)
Diarrhoea NOS	6/20 (30%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Dry mouth	1/20 (5%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Dyspepsia	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Dysphagia	3/20 (15%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Enterocolitis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Flatulence	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Gastric dilatation	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gastric haemorrhage	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gastric ileus	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gastrointestinal disorder	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gastrooesophageal reflux disease	1/20 (5%)		1/18 (5.6%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gingival bleeding	5/20 (25%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gingival pain	1/20 (5%)		0/18 (0%)		0/17 (0%)		2/33 (6.1%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Haemorrhoids	0/20 (0%)		0/18 (0%)		2/17 (11.8%)		3/33 (9.1%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hypoaesthesia oral	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Lip ulceration	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Loose stools	2/20 (10%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Melaena	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Mouth haemorrhage	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Mouth ulceration	2/20 (10%)		0/18 (0%)		0/17 (0%)		3/33 (9.1%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Nausea	14/20 (70%)		11/18 (61.1%)		9/17 (52.9%)		19/33 (57.6%)		16/27 (59.3%)		3/9 (33.3%)		3/7 (42.9%)		5/7 (71.4%)		6/6 (100%)
Neutropenic colitis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Obstruction gastric	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Odynophagia	2/20 (10%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Oral discomfort	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Oral mucosal petechiae	2/20 (10%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Oral pain	1/20 (5%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Perianal erythema	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Proctalgia	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Rectal haemorrhage	1/20 (5%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Rectal tenesmus	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Saliva altered	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Stomatitis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Tongue blistering	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Tongue oedema	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Vomiting	0/20 (0%)		12/18 (66.7%)		9/17 (52.9%)		13/33 (39.4%)		12/27 (44.4%)		4/9 (44.4%)		2/7 (28.6%)		3/7 (42.9%)		4/6 (66.7%)
Vomiting NOS	12/20 (60%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
General disorders
Asthenia	0/20 (0%)		5/18 (27.8%)		3/17 (17.6%)		6/33 (18.2%)		4/27 (14.8%)		0/9 (0%)		0/7 (0%)		2/7 (28.6%)		2/6 (33.3%)
Catheter site erythema	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Catheter site pain	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Chest pain	0/20 (0%)		0/18 (0%)		2/17 (11.8%)		3/33 (9.1%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Chills	0/20 (0%)		2/18 (11.1%)		1/17 (5.9%)		1/33 (3%)		2/27 (7.4%)		2/9 (22.2%)		1/7 (14.3%)		1/7 (14.3%)		1/6 (16.7%)
Fatigue	8/20 (40%)		7/18 (38.9%)		6/17 (35.3%)		12/33 (36.4%)		8/27 (29.6%)		3/9 (33.3%)		1/7 (14.3%)		4/7 (57.1%)		2/6 (33.3%)
Feeling cold	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
General physical health deterioration	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Generalised oedema	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Inflammation	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Injection site erythema	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Mucosal inflammation	0/20 (0%)		3/18 (16.7%)		1/17 (5.9%)		2/33 (6.1%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Nodule	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Non-cardiac chest pain	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Oedema	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		2/33 (6.1%)		3/27 (11.1%)		1/9 (11.1%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Oedema NOS	2/20 (10%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Oedema peripheral	8/20 (40%)		3/18 (16.7%)		4/17 (23.5%)		8/33 (24.2%)		6/27 (22.2%)		1/9 (11.1%)		1/7 (14.3%)		1/7 (14.3%)		1/6 (16.7%)
Pain	0/20 (0%)		2/18 (11.1%)		1/17 (5.9%)		5/33 (15.2%)		2/27 (7.4%)		2/9 (22.2%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Pain NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pyrexia	7/20 (35%)		7/18 (38.9%)		5/17 (29.4%)		7/33 (21.2%)		5/27 (18.5%)		4/9 (44.4%)		1/7 (14.3%)		1/7 (14.3%)		2/6 (33.3%)
Rigors	2/20 (10%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Submandibular mass	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Ulcer	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Vessel puncture site pain	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hepatobiliary disorders
Cholelithiasis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hepatic failure	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hepatic function abnormal NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hepatic steatosis	0/20 (0%)		1/18 (5.6%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hepatomegaly	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		1/6 (16.7%)
Hyperbilirubinaemia	2/20 (10%)		0/18 (0%)		2/17 (11.8%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Immune system disorders
Graft versus host disease	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Hypersensitivity	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Infections and infestations
Abscess	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Ano-rectal infection bacterial NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Aspergillosis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Bacteraemia	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Candidal infection NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Candidiasis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Carbuncle	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Catheter site infection	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cellulitis	1/20 (5%)		0/18 (0%)		1/17 (5.9%)		3/33 (9.1%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cystitis	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Ear infection	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Enterococcal infection	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Folliculitis	0/20 (0%)		2/18 (11.1%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Furuncle	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Herpes simplex	2/20 (10%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Herpes viral infection NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Herpes zoster	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Infection	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Influenza	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Lung infection	0/20 (0%)		1/18 (5.6%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Nasopharyngitis	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Oral candidiasis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		2/33 (6.1%)		2/27 (7.4%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Oral herpes	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pneumonia	0/20 (0%)		2/18 (11.1%)		3/17 (17.6%)		2/33 (6.1%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Puncture site infection	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Rash pustular	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Rhinitis	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Sepsis	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Sinusitis	0/20 (0%)		1/18 (5.6%)		1/17 (5.9%)		1/33 (3%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Sinusitis bacterial	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Skin infection	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Staphylococcal infection	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Upper respiratory tract infection	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		2/7 (28.6%)		1/6 (16.7%)
Upper respiratory tract infection NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Urinary tract infection	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		3/33 (9.1%)		4/27 (14.8%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Vaginal candidiasis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Viral infection NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Injury, poisoning and procedural complications
Blister	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Blood blister	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Contrast media reaction	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Contusion	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		2/33 (6.1%)		4/27 (14.8%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Excoriation	0/20 (0%)		1/18 (5.6%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Fall	1/20 (5%)		0/18 (0%)		3/17 (17.6%)		2/33 (6.1%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Head injury	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Joint injury	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Limb injury	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Limb injury NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Post procedural complication	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Post procedural pain	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Postoperative haematoma	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Skin laceration	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Subcutaneous haematoma	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Thermal burn	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Transfusion reaction	3/20 (15%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Investigations
Activated partial thromboplastin time prolonged	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Alanine aminotransferase increased	2/20 (10%)		2/18 (11.1%)		4/17 (23.5%)		0/33 (0%)		3/27 (11.1%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Aspartate aminotransferase increased	2/20 (10%)		3/18 (16.7%)		4/17 (23.5%)		0/33 (0%)		3/27 (11.1%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Blood alkaline phosphatase increased	2/20 (10%)		1/18 (5.6%)		2/17 (11.8%)		0/33 (0%)		3/27 (11.1%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Blood amylase increased	1/20 (5%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		1/7 (14.3%)		1/6 (16.7%)
Blood bilirubin increased	3/20 (15%)		3/18 (16.7%)		1/17 (5.9%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		1/7 (14.3%)		1/7 (14.3%)		0/6 (0%)
Blood creatinine increased	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		1/6 (16.7%)
Blood glucose increased	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Blood in stool	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Body temperature increased	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cardiac murmur NOS	3/20 (15%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Gamma-glutamyltransferase increased	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Haemoglobin decreased	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hepatic enzyme increased	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Lipase increased	1/20 (5%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Oxygen saturation decreased	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Prothrombin time prolonged	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Spleen palpable	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Weight decreased	1/20 (5%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
White blood cell count increased	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Metabolism and nutrition disorders
Acidosis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Alkalosis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Anorexia	5/20 (25%)		3/18 (16.7%)		2/17 (11.8%)		5/33 (15.2%)		4/27 (14.8%)		0/9 (0%)		1/7 (14.3%)		1/7 (14.3%)		0/6 (0%)
Decreased appetite	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		3/27 (11.1%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Dehydration	2/20 (10%)		2/18 (11.1%)		1/17 (5.9%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Diabetes mellitus	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Fluid retention	1/20 (5%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hypercalcaemia	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hyperglycaemia	0/20 (0%)		2/18 (11.1%)		3/17 (17.6%)		2/33 (6.1%)		4/27 (14.8%)		0/9 (0%)		1/7 (14.3%)		3/7 (42.9%)		1/6 (16.7%)
Hyperglycaemia NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hyperlipidaemia	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Hyperuricaemia	0/20 (0%)		0/18 (0%)		0/17 (0%)		3/33 (9.1%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		1/7 (14.3%)		1/6 (16.7%)
Hypoalbuminaemia	0/20 (0%)		2/18 (11.1%)		3/17 (17.6%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Hypocalcaemia	1/20 (5%)		3/18 (16.7%)		2/17 (11.8%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		1/7 (14.3%)		1/7 (14.3%)		1/6 (16.7%)
Hypokalaemia	5/20 (25%)		7/18 (38.9%)		6/17 (35.3%)		8/33 (24.2%)		3/27 (11.1%)		3/9 (33.3%)		1/7 (14.3%)		1/7 (14.3%)		2/6 (33.3%)
Hypomagnesaemia	3/20 (15%)		2/18 (11.1%)		2/17 (11.8%)		4/33 (12.1%)		4/27 (14.8%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Hyponatraemia	1/20 (5%)		4/18 (22.2%)		3/17 (17.6%)		3/33 (9.1%)		1/27 (3.7%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Hypophosphataemia	1/20 (5%)		1/18 (5.6%)		3/17 (17.6%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Malnutrition	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/20 (10%)		0/18 (0%)		1/17 (5.9%)		3/33 (9.1%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Back pain	3/20 (15%)		2/18 (11.1%)		1/17 (5.9%)		3/33 (9.1%)		3/27 (11.1%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Bone pain	2/20 (10%)		1/18 (5.6%)		2/17 (11.8%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Buttock pain	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Groin pain	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Intervertebral disc disorder	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Intervertebral disc protrusion	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Muscle cramp	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Muscle spasms	0/20 (0%)		2/18 (11.1%)		0/17 (0%)		0/33 (0%)		3/27 (11.1%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		1/6 (16.7%)
Muscular weakness	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Musculoskeletal chest pain	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Musculoskeletal pain	0/20 (0%)		1/18 (5.6%)		2/17 (11.8%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		2/7 (28.6%)		2/7 (28.6%)		1/6 (16.7%)
Myalgia	2/20 (10%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Neck pain	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Nodule on extremity	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pain in extremity	2/20 (10%)		1/18 (5.6%)		1/17 (5.9%)		3/33 (9.1%)		0/27 (0%)		1/9 (11.1%)		2/7 (28.6%)		0/7 (0%)		1/6 (16.7%)
Pain in jaw	1/20 (5%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Tendon disorder	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign lung neoplasm	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Central nervous system leukaemia	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Leukaemia cutis	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Metastases to central nervous system	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Nervous system disorders
Amnesia	0/20 (0%)		0/18 (0%)		0/17 (0%)		2/33 (6.1%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Ataxia	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Brain mass	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Disturbance in attention	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Dizziness	2/20 (10%)		2/18 (11.1%)		1/17 (5.9%)		2/33 (6.1%)		7/27 (25.9%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		2/6 (33.3%)
Dysgeusia	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Headache	7/20 (35%)		5/18 (27.8%)		2/17 (11.8%)		4/33 (12.1%)		5/27 (18.5%)		3/9 (33.3%)		3/7 (42.9%)		3/7 (42.9%)		2/6 (33.3%)
Hemiparesis	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hypogeusia	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Lethargy	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Loss of consciousness	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Neurological symptom	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Paraesthesia	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Peroneal nerve palsy	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Postictal state	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Sinus headache	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Sleep apnoea syndrome	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Somnolence	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Tremor	2/20 (10%)		0/18 (0%)		0/17 (0%)		2/33 (6.1%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Psychiatric disorders
Agitation	1/20 (5%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Anxiety	4/20 (20%)		3/18 (16.7%)		1/17 (5.9%)		3/33 (9.1%)		3/27 (11.1%)		1/9 (11.1%)		0/7 (0%)		1/7 (14.3%)		1/6 (16.7%)
Confusional state	2/20 (10%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Depression	2/20 (10%)		1/18 (5.6%)		0/17 (0%)		2/33 (6.1%)		3/27 (11.1%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Disorientation	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Hallucination NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Insomnia	2/20 (10%)		1/18 (5.6%)		2/17 (11.8%)		3/33 (9.1%)		4/27 (14.8%)		2/9 (22.2%)		2/7 (28.6%)		0/7 (0%)		3/6 (50%)
Restlessness	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Sleep disorder	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Renal and urinary disorders
Bladder pain	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Haematuria	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Renal failure	0/20 (0%)		1/18 (5.6%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Urge incontinence	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Urinary incontinence	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Urinary retention	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Reproductive system and breast disorders
Pelvic pain	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Vaginal haemorrhage	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Breath sounds decreased	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Cough	7/20 (35%)		4/18 (22.2%)		4/17 (23.5%)		6/33 (18.2%)		3/27 (11.1%)		2/9 (22.2%)		0/7 (0%)		1/7 (14.3%)		2/6 (33.3%)
Dyspnoea	3/20 (15%)		5/18 (27.8%)		2/17 (11.8%)		8/33 (24.2%)		8/27 (29.6%)		2/9 (22.2%)		3/7 (42.9%)		0/7 (0%)		1/6 (16.7%)
Dyspnoea exertional	1/20 (5%)		1/18 (5.6%)		0/17 (0%)		4/33 (12.1%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Epistaxis	2/20 (10%)		2/18 (11.1%)		0/17 (0%)		1/33 (3%)		4/27 (14.8%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Haemoptysis	1/20 (5%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Hoarseness	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hypoxia	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Increased upper airway secretion	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Lung infiltration	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Lung infiltration NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Nasal congestion	1/20 (5%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		1/27 (3.7%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Nasal dryness	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pharyngolaryngeal pain	1/20 (5%)		1/18 (5.6%)		0/17 (0%)		4/33 (12.1%)		2/27 (7.4%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Pleural effusion	1/20 (5%)		0/18 (0%)		3/17 (17.6%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Pleuritic pain	1/20 (5%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		1/7 (14.3%)		0/7 (0%)		0/6 (0%)
Postnasal drip	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Productive cough	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pulmonary oedema NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Rales	1/20 (5%)		0/18 (0%)		1/17 (5.9%)		2/33 (6.1%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Respiratory failure	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Rhonchi	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Sinus congestion	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Tachypnoea	0/20 (0%)		1/18 (5.6%)		1/17 (5.9%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Tonsillar ulcer	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Wheezing	1/20 (5%)		0/18 (0%)		1/17 (5.9%)		1/33 (3%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Skin and subcutaneous tissue disorders
Blister	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Blood blister	0/20 (0%)		2/18 (11.1%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Contusion	2/20 (10%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Dry skin	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Ecchymosis	3/20 (15%)		2/18 (11.1%)		1/17 (5.9%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		2/7 (28.6%)		0/7 (0%)		1/6 (16.7%)
Eczema	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Erythema	3/20 (15%)		0/18 (0%)		1/17 (5.9%)		2/33 (6.1%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hyperhidrosis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		2/33 (6.1%)		1/27 (3.7%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hyperkeratosis	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Night sweats	2/20 (10%)		1/18 (5.6%)		1/17 (5.9%)		3/33 (9.1%)		2/27 (7.4%)		1/9 (11.1%)		0/7 (0%)		3/7 (42.9%)		0/6 (0%)
Penile ulceration	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Petechiae	0/20 (0%)		4/18 (22.2%)		1/17 (5.9%)		2/33 (6.1%)		2/27 (7.4%)		1/9 (11.1%)		0/7 (0%)		1/7 (14.3%)		2/6 (33.3%)
Psoriasis	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Purpura NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Rash	0/20 (0%)		1/18 (5.6%)		1/17 (5.9%)		1/33 (3%)		5/27 (18.5%)		2/9 (22.2%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Rash erythematous	1/20 (5%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		1/7 (14.3%)		1/6 (16.7%)
Rash maculo-papular	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Rash papular	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		1/7 (14.3%)		0/6 (0%)
Skin discolouration	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Skin hyperpigmentation	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Skin lesion	0/20 (0%)		1/18 (5.6%)		1/17 (5.9%)		0/33 (0%)		1/27 (3.7%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Skin lesion NOS	1/20 (5%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Skin ulcer	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		1/6 (16.7%)
Subcutaneous nodule	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Urticaria NOS	2/20 (10%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Surgical and medical procedures
Sinus operation	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Vascular disorders
Haematoma	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		3/33 (9.1%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		1/7 (14.3%)		1/6 (16.7%)
Haematoma NOS	3/20 (15%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hot flush	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Hypertension	0/20 (0%)		0/18 (0%)		0/17 (0%)		1/33 (3%)		2/27 (7.4%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		2/6 (33.3%)
Hypotension	0/20 (0%)		2/18 (11.1%)		3/17 (17.6%)		2/33 (6.1%)		1/27 (3.7%)		1/9 (11.1%)		2/7 (28.6%)		0/7 (0%)		0/6 (0%)
Hypotension NOS	2/20 (10%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Jugular vein thrombosis	0/20 (0%)		0/18 (0%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		1/9 (11.1%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Pallor	0/20 (0%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		1/7 (14.3%)		1/7 (14.3%)		0/6 (0%)
Petechiae	3/20 (15%)		0/18 (0%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Phlebitis	0/20 (0%)		0/18 (0%)		2/17 (11.8%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Thrombophlebitis	0/20 (0%)		1/18 (5.6%)		1/17 (5.9%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)
Wound haemorrhage	0/20 (0%)		1/18 (5.6%)		0/17 (0%)		0/33 (0%)		0/27 (0%)		0/9 (0%)		0/7 (0%)		0/7 (0%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

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 or disclosure of trial results in their entirety.

Results Point of Contact

Name/Title	Study Director
Organization	Novartis
Phone	862-778-8300
Email

Responsible Party:

Novartis Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT00045942

Other Study ID Numbers:

CPKC412A2104
NCT00045578
NCT00977782

First Posted:

Sep 18, 2002

Last Update Posted:

Aug 11, 2017

Last Verified:

Aug 1, 2017

PKC412 in Participants With Acute Myeloid Leukemia or With Myelodysplastic Syndrome (CPKC412A2104 Core); and PKC412 in Participants With Acute Myeloid Leukemia or With Myelodysplastic Syndrome With Either Wild Type or Mutated FMS-like Tyrosine Kinase 3 (FLT3) (CPKC412A2104E1 and CPKC412A2104E2)

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