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Clinical Trial Results:
A phase Ib/II study investigating the combination of everolimus with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer

Summary
EudraCT number	2006-001596-37
Trial protocol	BE
Global end of trial date	10 Apr 2013

Results information
Results version number	v1(current)
This version publication date	13 Jul 2016
First version publication date	05 Aug 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CRAD001J2101

ISRCTN number

US NCT number

NCT00426556

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

10 Apr 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Apr 2013

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this phase II study was to evaluate the efficacy of the dose level/regimen of everolimus recommended from the Phase I with trastuzumab and paclitaxel (PT) therapy in patients with HER2-overexpressing metastatic breast cancer whose disease progressed on/after trastuzumab mono-and/or combination therapy based on the evaluation of objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Objective response rate (ORR) was defined as the proportion of patients with a best overall response (BOR) of complete response (CR) or partial response (PR). Only patients with measurable disease (the presence of at least one measurable lesion) at baseline were included in the study. CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. In addition, the doses and schedules of everolimus investigated in this study were based on previous safety experience in earlier everolimus phase I oncology studies that showed everolimus monotherapy to be pharmacodynamically active and satisfactorily tolerated in two different regimens-weekly at doses of 50 to 70 mg and daily at doses of 5 and 10 mg.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Jul 2007

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 27

Country: Number of subjects enrolled

Spain: 3

Country: Number of subjects enrolled

Netherlands: 4

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

France: 51

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Based on the results of the Phase I portion of this study, in addition to all available information on daily and weekly everolimus regimen in breast cancer and other tumors, all patients in the Phase II portion of the study were allocated to one arm to receive the recommended everolimus dose of 10 mg daily in combination with PT.

Period 1 title

Phase I and Phase II Core Phase

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

RAD001 5mg + PT, Daily

Arm description

Daily dosing schedule of everolimus 5 mg plus weekly paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

RAD001

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 5 mg everolimus once daily.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered weekly in a 28-day cycle.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab was administered weekly in a 28-day cycle.

RAD001 10 mg + PT, Daily

Arm description

Daily dosing schedule of everolimus 10 mg plus weekly paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

RAD001

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 10 mg everolimus once daily.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered weekly in a 28-day cycle.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab was administered weekly in a 28-day cycle.

RAD001 30 mg + PT, Weekly

Arm description

Weekly dosing schedule of everolimus 30 mg plus paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab.

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

RAD001

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 30 mg everolimus once daily.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered weekly in a 28-day cycle.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab was administered weekly in a 28-day cycle.

RAD001 10 mg + PT, Daily (Phase 2)

Arm description

Daily dosing schedule of everolimus 10 mg plus weekly paclitaxel plus trastuzumab. PT = Paclitaxel and Trastuzumab

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

RAD001

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 10 mg everolimus once daily.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered weekly in a 28-day cycle.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab was administered weekly in a 28-day cycle.

Number of subjects in period 1	RAD001 5mg + PT, Daily	RAD001 10 mg + PT, Daily	RAD001 30 mg + PT, Weekly	RAD001 10 mg + PT, Daily (Phase 2)
Started	6	17	10	55
Completed	5	7	7	28
Not completed	1	10	3	27
Consent withdrawn by subject	-	-	-	3
Adverse Event	1	3	1	8
Death	-	1	-	-
Disease Progression	-	6	2	16

Period 2 title

Phase I and Phase II Extension Phase

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

RAD001 5 mg + PT, Daily

Arm description

Daily dosing schedule of everolimus 5 mg plus weekly paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

RAD001

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 5 mg everolimus once daily.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered weekly in a 28-day cycle.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab was administered weekly in a 28-day cycle.

RAD001 10 mg + PT, Daily

Arm description

Daily dosing schedule of everolimus 10 mg plus weekly paclitaxel plus trastuzumab. PT = Paclitaxel and Trastuzumab

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

RAD001

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 10 mg everolimus once daily.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered weekly in a 28-day cycle.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab was administered weekly in a 28-day cycle.

RAD001 30 mg + PT, Weekly

Arm description

Weekly dosing schedule of everolimus 30 mg plus paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab.

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

RAD001

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 30 mg everolimus once daily.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered weekly in a 28-day cycle.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab was administered weekly in a 28-day cycle.

RAD001 10 mg + PT, Daily (Phase 2)

Arm description

Daily dosing schedule of everolimus 10 mg plus weekly paclitaxel plus trastuzumab. PT = Paclitaxel and Trastuzumab

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

RAD001

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received 10 mg everolimus once daily.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel was administered weekly in a 28-day cycle.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab was administered weekly in a 28-day cycle.

Number of subjects in period 2 ^[1]	RAD001 5 mg + PT, Daily	RAD001 10 mg + PT, Daily	RAD001 30 mg + PT, Weekly	RAD001 10 mg + PT, Daily (Phase 2)
Started	5	7	7	24
Completed	0	1	0	1
Not completed	5	6	7	23
Adverse Event	-	1	1	2
Disease Progression	5	5	6	21

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Of the 28 patients in RAD001 10 mg+ PT, daily (Phase 2) that completed Phase I, 4 patients did not enter the Phase II Extension Phase.

Baseline characteristics

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Reporting group title

RAD001 5mg + PT, Daily

Reporting group description

Daily dosing schedule of everolimus 5 mg plus weekly paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab

Reporting group title

RAD001 10 mg + PT, Daily

Reporting group description

Daily dosing schedule of everolimus 10 mg plus weekly paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab

Reporting group title

RAD001 30 mg + PT, Weekly

Reporting group description

Weekly dosing schedule of everolimus 30 mg plus paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab.

Reporting group title

RAD001 10 mg + PT, Daily (Phase 2)

Reporting group description

Daily dosing schedule of everolimus 10 mg plus weekly paclitaxel plus trastuzumab. PT = Paclitaxel and Trastuzumab

Reporting group values	RAD001 5mg + PT, Daily	RAD001 10 mg + PT, Daily	RAD001 30 mg + PT, Weekly	RAD001 10 mg + PT, Daily (Phase 2)	Total
Number of subjects	6	17	10	55	88
Age categorical
Units: Subjects
< 65	6	13	6	46	71
>= 65	0	4	4	9	17
Gender categorical
Units: Subjects
Female	6	17	10	55	88
WHO Performance Status
0=Fully active, able to carry out normal activity without restriction, 1=Restricted in physical strenuous activity but ambulatory and able to carry work of a light or sedentary nature e.g. light house work, office work.
Units: Subjects
PS=0	4	5	4	36	49
PS=1	2	12	6	19	39

End points

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Reporting group title

RAD001 5mg + PT, Daily

Reporting group description

Daily dosing schedule of everolimus 5 mg plus weekly paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab

Reporting group title

RAD001 10 mg + PT, Daily

Reporting group description

Daily dosing schedule of everolimus 10 mg plus weekly paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab

Reporting group title

RAD001 30 mg + PT, Weekly

Reporting group description

Weekly dosing schedule of everolimus 30 mg plus paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab.

Reporting group title

RAD001 10 mg + PT, Daily (Phase 2)

Reporting group description

Daily dosing schedule of everolimus 10 mg plus weekly paclitaxel plus trastuzumab. PT = Paclitaxel and Trastuzumab

Reporting group title

RAD001 5 mg + PT, Daily

Reporting group description

Daily dosing schedule of everolimus 5 mg plus weekly paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab

Reporting group title

RAD001 10 mg + PT, Daily

Reporting group description

Daily dosing schedule of everolimus 10 mg plus weekly paclitaxel plus trastuzumab. PT = Paclitaxel and Trastuzumab

Reporting group title

RAD001 30 mg + PT, Weekly

Reporting group description

Weekly dosing schedule of everolimus 30 mg plus paclitaxel plus trastuzumab. PT = paclitaxel and trastuzumab.

Reporting group title

RAD001 10 mg + PT, Daily (Phase 2)

Reporting group description

Daily dosing schedule of everolimus 10 mg plus weekly paclitaxel plus trastuzumab. PT = Paclitaxel and Trastuzumab

Primary: Overall Response Rate: RAD001 10 mg + PT, Daily (Phase 2)

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End point title

Overall Response Rate: RAD001 10 mg + PT, Daily (Phase 2) ^[1] ^[2]

End point description

The primary objective in Phase II was to evaluate efficacy of the dose level/regimen of everolimus from Phase I with PT therapy in patients with HER2-overexpressing metastatic breast cancer whose disease progressed on/after trastuzumab mono-and/or combination therapy based on evaluation of objective response rate (ORR: defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) per RECIST). Only patients with measurable disease (the presence of at least one measurable lesion) at baseline were included in the study. CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. This included the Full Analysis Set, which consisted of all patients who received a least one dose of any one compound of study treatment. Patients were analyzed according to the everolimus dose level to which they enrolled.

End point type

Primary

End point timeframe

Every 8 to 9 weeks.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: A Simon two-stage design was used to assess the efficacy of the recommended dose. This design provides rules for a decision to be based on number of responders observed either to stop or to proceed with the second stage. Responses were summarized in terms of percentage rates along with exact 2-sided 95% confidence intervals. The Clopper-Pearson method was used to determine the confidence intervals.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only RAD001 10 mg + PT, Daily (Phase 2) was included in this analysis.

End point values	RAD001 10 mg + PT, Daily (Phase 2)
Number of subjects analysed	55 ^[3]
Units: Percentage of Participants
number (not applicable)
Objective Response Rate	21.8

Notes
[3] - Full analysis set

No statistical analyses for this end point

Secondary: Best Overall Response

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End point title

Best Overall Response ^[4]

End point description

Best overall response rate (BOR) was determined based on investigator assessment of overall lesion response using RECIST criteria guidelines. BOR = objective responses rate (ORR), disease control rate (DCR) or clinical benefit rate (CBR). ORR = (complete response (CR) or partial response(PR); DCR = (CR or PR or Stable disease (SD); CBR = (CR or PR od SD >= 24 weeks).CR = Disappearance of all target lesions; PR = At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for partial disease (PD). PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.

End point type

Secondary

End point timeframe

Every 8 to 9 weeks .

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: RAD001 10 mg + PT, Daily (Phase 2) was not included in this analysis.

End point values	RAD001 5mg + PT, Daily	RAD001 10 mg + PT, Daily	RAD001 30 mg + PT, Weekly
Number of subjects analysed	6 ^[5]	17 ^[6]	10 ^[7]
Units: Percentage of Participants
number (not applicable)
Objective Response Rate (ORR)	83.3	23.5	30
Disease Control Rate (DCR)	83.3	82.4	80
Clinical Benefit Rate (CBR)	83.3	47.1	70

Notes
[5] - Full analysis set
[6] - Full analysis set
[7] - Full analysis set

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS): RAD001 10 mg + PT, Daily (Phase 2)

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End point title

Progression Free Survival (PFS): RAD001 10 mg + PT, Daily (Phase 2) ^[8]

End point description

PFS is defined as the time from start of treatment to the date of first documented progression or death due to any cause. If a patient has not had an event, PFS will be censored at the date of last adequate tumor assessment. The Full Analysis Set was used, which consisted of all patients who received a least one dose of any one compound of the study treatment. Patients were analyzed according to the everolimus dose level to which they enrolled.

End point type

Secondary

End point timeframe

Every 8 to 9 weeks.

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only RAD001 10 mg + PT, Daily (Phase 2) was included in this analysis.

End point values	RAD001 10 mg + PT, Daily (Phase 2)
Number of subjects analysed	55 ^[9]
Units: Months
median (confidence interval 95%)
Progression Free Survival (PFS)	5.52 (4.99 to 7.69)

Notes
[9] - Full analysis set

No statistical analyses for this end point

Secondary: Overall Survival (OS): RAD001 10 mg + PT, Daily (Phase 2)

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End point title

Overall Survival (OS): RAD001 10 mg + PT, Daily (Phase 2) ^[10]

End point description

Overall survival (OS) is defined as the time from start of treatment to the date of death due to any cause. If a patient is not known to have died, survival was censored at the last date of contact. OS was to be reported at extension and after 3-year follow-up. The Kaplan-Meier median was used to analyze the OS. The Full Analysis Set (FAS) was used, which consisted of all patients who received a least one dose of any one compound of the study treatment. Patients were analyzed according to the everolimus dose level to which they enrolled.

End point type

Secondary

End point timeframe

Every 3 months

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only RAD001 10 mg + PT, Daily (Phase 2) was included in this analysis.

End point values	RAD001 10 mg + PT, Daily (Phase 2)
Number of subjects analysed	55 ^[11]
Units: Months
median (confidence interval 95%)
Phase II: Overall Survival (OS)	18.07 (12.85 to 24.11)

Notes
[11] - Full analysis set

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Phase I - Everolimus 5mg Daily + HT

Reporting group description

Phase I - Everolimus 5mg Daily + HT

Reporting group title

Phase II - Everolimus 10mg Daily + HT

Reporting group description

Phase II - Everolimus 10mg Daily + HT

Reporting group title

Phase I - Everolimus 30mg Weekly + HT

Reporting group description

Phase I - Everolimus 30mg Weekly + HT

Reporting group title

Phase I - Everolimus 10mg Daily + HT

Reporting group description

Phase I - Everolimus 10mg Daily + HT

Serious adverse events	Phase I - Everolimus 5mg Daily + HT	Phase II - Everolimus 10mg Daily + HT	Phase I - Everolimus 30mg Weekly + HT	Phase I - Everolimus 10mg Daily + HT
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 6 (50.00%)	26 / 55 (47.27%)	7 / 10 (70.00%)	6 / 17 (35.29%)
number of deaths (all causes)	1	3	0	1
number of deaths resulting from adverse events	0	1	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jugular vein thrombosis
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	6 / 55 (10.91%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	3 / 6	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Alveolitis allergic
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tracheal obstruction extrinsic
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
White blood cell count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardio-respiratory arrest
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain oedema
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coma
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Grand mal convulsion
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial pressure increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Visual impairment
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	2 / 3	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	4 / 55 (7.27%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 5	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stenosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pruritus
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Monarthritis
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchopneumonia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	2 / 10 (20.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1
Septic shock
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Cell death
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vitamin D deficiency
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase I - Everolimus 5mg Daily + HT	Phase II - Everolimus 10mg Daily + HT	Phase I - Everolimus 30mg Weekly + HT	Phase I - Everolimus 10mg Daily + HT
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	55 / 55 (100.00%)	10 / 10 (100.00%)	17 / 17 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0
Cancer pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Ear neoplasm
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Vascular disorders
Arterial thrombosis limb
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Hot flush
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	4	0	1
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	2	1	0
Lymphoedema
subjects affected / exposed	1 / 6 (16.67%)	5 / 55 (9.09%)	1 / 10 (10.00%)	3 / 17 (17.65%)
occurrences all number	2	5	1	4
General disorders and administration site conditions
Adverse drug reaction
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Asthenia
subjects affected / exposed	4 / 6 (66.67%)	28 / 55 (50.91%)	6 / 10 (60.00%)	8 / 17 (47.06%)
occurrences all number	11	52	12	12
Chest pain
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	2	1	1
Chills
subjects affected / exposed	1 / 6 (16.67%)	2 / 55 (3.64%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	1	2	1	1
Face oedema
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	3	0	0
Facial pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Fatigue
subjects affected / exposed	2 / 6 (33.33%)	12 / 55 (21.82%)	3 / 10 (30.00%)	4 / 17 (23.53%)
occurrences all number	2	15	3	5
Gait disturbance
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	2 / 17 (11.76%)
occurrences all number	0	0	1	2
General physical health deterioration
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	1	1	0
Influenza like illness
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	1	1	0
Injection site pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Non-cardiac chest pain
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	3	0	1
Oedema
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	1	0	2
Oedema peripheral
subjects affected / exposed	2 / 6 (33.33%)	13 / 55 (23.64%)	3 / 10 (30.00%)	11 / 17 (64.71%)
occurrences all number	3	21	4	15
Xerosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	0	2
Pyrexia
subjects affected / exposed	4 / 6 (66.67%)	19 / 55 (34.55%)	1 / 10 (10.00%)	7 / 17 (41.18%)
occurrences all number	7	25	1	8
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	2	1	1
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Genital discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Metrorrhagia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Vaginal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 6 (16.67%)	20 / 55 (36.36%)	2 / 10 (20.00%)	6 / 17 (35.29%)
occurrences all number	2	27	3	8
Dysphonia
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	1 / 10 (10.00%)	3 / 17 (17.65%)
occurrences all number	0	3	1	3
Dyspnoea
subjects affected / exposed	2 / 6 (33.33%)	9 / 55 (16.36%)	2 / 10 (20.00%)	6 / 17 (35.29%)
occurrences all number	2	9	6	7
Epistaxis
subjects affected / exposed	3 / 6 (50.00%)	16 / 55 (29.09%)	3 / 10 (30.00%)	11 / 17 (64.71%)
occurrences all number	6	29	3	14
Hypoxia
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	0	2
Larynx irritation
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Lung disorder
subjects affected / exposed	1 / 6 (16.67%)	3 / 55 (5.45%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	3	0	1
Nasal dryness
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	2
Obstructive airways disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 6 (0.00%)	6 / 55 (10.91%)	1 / 10 (10.00%)	2 / 17 (11.76%)
occurrences all number	0	8	1	2
Pharyngeal ulceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Pleural effusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1	1
Productive cough
subjects affected / exposed	2 / 6 (33.33%)	0 / 55 (0.00%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	2	0	1	1
Rhinitis allergic
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Rhinorrhoea
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Sinus congestion
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	0	2
Tracheal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Confusional state
subjects affected / exposed	1 / 6 (16.67%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	1	0	0
Depression
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Insomnia
subjects affected / exposed	0 / 6 (0.00%)	6 / 55 (10.91%)	2 / 10 (20.00%)	4 / 17 (23.53%)
occurrences all number	0	6	2	4
Mood altered
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	1	1	0
Sleep disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	2 / 55 (3.64%)	1 / 10 (10.00%)	2 / 17 (11.76%)
occurrences all number	1	4	1	2
Aspartate aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	3 / 55 (5.45%)	0 / 10 (0.00%)	4 / 17 (23.53%)
occurrences all number	1	5	0	4
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Blood creatine phosphokinase MB increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Blood creatinine increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	1	1	1
Blood magnesium decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Blood phosphorus decreased
subjects affected / exposed	1 / 6 (16.67%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	4	0	0
Blood potassium decreased
subjects affected / exposed	1 / 6 (16.67%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	4	0	0
Carbon monoxide diffusing capacity decreased
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	2	1	0
Echography abnormal
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Ejection fraction decreased
subjects affected / exposed	1 / 6 (16.67%)	2 / 55 (3.64%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	1	3	1	1
Electrocardiogram abnormal
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Haemoglobin decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	3	0	1
Transaminases increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Troponin I increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Weight decreased
subjects affected / exposed	2 / 6 (33.33%)	11 / 55 (20.00%)	2 / 10 (20.00%)	3 / 17 (17.65%)
occurrences all number	2	15	2	7
Weight increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
White blood cell count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	2 / 10 (20.00%)	0 / 17 (0.00%)
occurrences all number	0	0	10	0
Injury, poisoning and procedural complications
Pubis fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Radiation pneumonitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Palpitations
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Pericardial effusion
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	1	1	1
Tachycardia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	4 / 55 (7.27%)	0 / 10 (0.00%)	3 / 17 (17.65%)
occurrences all number	0	5	0	3
Dysaesthesia
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1	1
Dysgeusia
subjects affected / exposed	0 / 6 (0.00%)	4 / 55 (7.27%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	4	0	2
Headache
subjects affected / exposed	1 / 6 (16.67%)	23 / 55 (41.82%)	3 / 10 (30.00%)	7 / 17 (41.18%)
occurrences all number	1	39	6	14
Horner's syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Hypoaesthesia
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	3	1	0
Hypokinesia
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	2	0	1
Neurotoxicity
subjects affected / exposed	1 / 6 (16.67%)	6 / 55 (10.91%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	2	8	0	1
Neuropathy peripheral
subjects affected / exposed	1 / 6 (16.67%)	20 / 55 (36.36%)	1 / 10 (10.00%)	2 / 17 (11.76%)
occurrences all number	1	22	1	2
Paraesthesia
subjects affected / exposed	2 / 6 (33.33%)	6 / 55 (10.91%)	4 / 10 (40.00%)	6 / 17 (35.29%)
occurrences all number	4	10	4	9
Peripheral sensory neuropathy
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	1 / 10 (10.00%)	2 / 17 (11.76%)
occurrences all number	0	4	1	2
Sciatica
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Sinus headache
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	1	1	0
Somnolence
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	1	1	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 6 (83.33%)	19 / 55 (34.55%)	4 / 10 (40.00%)	5 / 17 (29.41%)
occurrences all number	11	29	5	10
Anaemia macrocytic
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0
Febrile neutropenia
subjects affected / exposed	1 / 6 (16.67%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	1	0	0
Leukopenia
subjects affected / exposed	2 / 6 (33.33%)	12 / 55 (21.82%)	2 / 10 (20.00%)	9 / 17 (52.94%)
occurrences all number	2	20	2	21
Lymphopenia
subjects affected / exposed	2 / 6 (33.33%)	11 / 55 (20.00%)	5 / 10 (50.00%)	7 / 17 (41.18%)
occurrences all number	4	18	27	16
Microcytosis
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0
Neutropenia
subjects affected / exposed	4 / 6 (66.67%)	20 / 55 (36.36%)	5 / 10 (50.00%)	12 / 17 (70.59%)
occurrences all number	11	32	13	42
Thrombocytopenia
subjects affected / exposed	1 / 6 (16.67%)	9 / 55 (16.36%)	0 / 10 (0.00%)	3 / 17 (17.65%)
occurrences all number	1	16	0	4
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	0	1
Vertigo
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	0 / 10 (0.00%)	3 / 17 (17.65%)
occurrences all number	0	2	0	4
Tinnitus
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	2
Eye disorders
Diplopia
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	3	0	0
Dry eye
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	1	1	1
Eye inflammation
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0
Eye pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Lacrimation increased
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	2	0	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 6 (50.00%)	8 / 55 (14.55%)	2 / 10 (20.00%)	3 / 17 (17.65%)
occurrences all number	3	12	4	4
Abdominal pain lower
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Aphthous stomatitis
subjects affected / exposed	0 / 6 (0.00%)	9 / 55 (16.36%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	11	0	3
Ascites
subjects affected / exposed	1 / 6 (16.67%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	1	0	0
Abdominal pain upper
subjects affected / exposed	1 / 6 (16.67%)	5 / 55 (9.09%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	2	5	0	2
Constipation
subjects affected / exposed	2 / 6 (33.33%)	13 / 55 (23.64%)	5 / 10 (50.00%)	8 / 17 (47.06%)
occurrences all number	5	15	6	9
Diarrhoea
subjects affected / exposed	4 / 6 (66.67%)	30 / 55 (54.55%)	7 / 10 (70.00%)	11 / 17 (64.71%)
occurrences all number	14	69	10	18
Dental caries
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	2 / 10 (20.00%)	1 / 17 (5.88%)
occurrences all number	0	1	2	1
Dyspepsia
subjects affected / exposed	3 / 6 (50.00%)	4 / 55 (7.27%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	3	6	2	0
Dry mouth
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Gastrointestinal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Gastritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Gastrointestinal toxicity
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	1 / 10 (10.00%)	2 / 17 (11.76%)
occurrences all number	0	2	1	2
Gingival hypertrophy
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Gingival pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	2
Gingivitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Haemorrhoids
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Mouth ulceration
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	2	0	1
Nausea
subjects affected / exposed	3 / 6 (50.00%)	21 / 55 (38.18%)	5 / 10 (50.00%)	7 / 17 (41.18%)
occurrences all number	7	31	15	10
Odynophagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Oral disorder
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0
Oral pain
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	1 / 10 (10.00%)	2 / 17 (11.76%)
occurrences all number	0	3	1	2
Stomatitis
subjects affected / exposed	3 / 6 (50.00%)	42 / 55 (76.36%)	8 / 10 (80.00%)	16 / 17 (94.12%)
occurrences all number	14	84	22	33
Tooth loss
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Vomiting
subjects affected / exposed	2 / 6 (33.33%)	12 / 55 (21.82%)	4 / 10 (40.00%)	5 / 17 (29.41%)
occurrences all number	12	16	12	7
Hepatobiliary disorders
Hepatic steatosis
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0
Cytolytic hepatitis
subjects affected / exposed	2 / 6 (33.33%)	2 / 55 (3.64%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	2	3	1	0
Hepatomegaly
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	0	2
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0
Alopecia
subjects affected / exposed	4 / 6 (66.67%)	15 / 55 (27.27%)	5 / 10 (50.00%)	6 / 17 (35.29%)
occurrences all number	5	16	5	6
Dermatitis acneiform
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	3 / 17 (17.65%)
occurrences all number	0	0	1	4
Dry skin
subjects affected / exposed	3 / 6 (50.00%)	6 / 55 (10.91%)	2 / 10 (20.00%)	2 / 17 (11.76%)
occurrences all number	3	8	2	2
Eczema
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	0	2
Erythema
subjects affected / exposed	0 / 6 (0.00%)	10 / 55 (18.18%)	2 / 10 (20.00%)	2 / 17 (11.76%)
occurrences all number	0	12	2	2
Hyperkeratosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1	1
Nail disorder
subjects affected / exposed	2 / 6 (33.33%)	6 / 55 (10.91%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	7	0	0
Nail toxicity
subjects affected / exposed	0 / 6 (0.00%)	6 / 55 (10.91%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	9	1	1
Onycholysis
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Onychomadesis
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	1	1	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Pigmentation disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Pruritus
subjects affected / exposed	0 / 6 (0.00%)	5 / 55 (9.09%)	2 / 10 (20.00%)	1 / 17 (5.88%)
occurrences all number	0	5	7	1
Rash
subjects affected / exposed	2 / 6 (33.33%)	26 / 55 (47.27%)	3 / 10 (30.00%)	8 / 17 (47.06%)
occurrences all number	3	36	3	11
Rash maculo-papular
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Rash vesicular
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Skin exfoliation
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Skin irritation
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Skin mass
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Skin toxicity
subjects affected / exposed	0 / 6 (0.00%)	4 / 55 (7.27%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	4	0	1
Skin ulcer
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1	1
Urticaria
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	3	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	1 / 10 (10.00%)	2 / 17 (11.76%)
occurrences all number	0	2	1	2
Haematuria
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	3	0	0
Pollakiuria
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	1	1	0
Proteinuria
subjects affected / exposed	1 / 6 (16.67%)	1 / 55 (1.82%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	2	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 6 (33.33%)	10 / 55 (18.18%)	2 / 10 (20.00%)	6 / 17 (35.29%)
occurrences all number	2	11	3	6
Back pain
subjects affected / exposed	2 / 6 (33.33%)	7 / 55 (12.73%)	1 / 10 (10.00%)	2 / 17 (11.76%)
occurrences all number	2	7	1	2
Bone pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Muscle spasms
subjects affected / exposed	0 / 6 (0.00%)	8 / 55 (14.55%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	8	0	2
Muscular weakness
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	3	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	3	0	2
Myalgia
subjects affected / exposed	4 / 6 (66.67%)	10 / 55 (18.18%)	1 / 10 (10.00%)	2 / 17 (11.76%)
occurrences all number	6	12	1	2
Musculoskeletal pain
subjects affected / exposed	1 / 6 (16.67%)	9 / 55 (16.36%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	1	10	1	1
Neck pain
subjects affected / exposed	1 / 6 (16.67%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	2	1	0	1
Pain in extremity
subjects affected / exposed	0 / 6 (0.00%)	4 / 55 (7.27%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	5	0	3
Tendon pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	2
Infections and infestations
Acute tonsillitis
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	3	0	0
Bronchitis
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	2	0	4
Candidiasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Clostridial infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	0	1
Cystitis
subjects affected / exposed	1 / 6 (16.67%)	1 / 55 (1.82%)	2 / 10 (20.00%)	0 / 17 (0.00%)
occurrences all number	1	1	4	0
Device related infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	2	0
Ear infection
subjects affected / exposed	1 / 6 (16.67%)	2 / 55 (3.64%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	2	0	0
Erysipelas
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1	1
Escherichia urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Folliculitis
subjects affected / exposed	1 / 6 (16.67%)	1 / 55 (1.82%)	1 / 10 (10.00%)	4 / 17 (23.53%)
occurrences all number	1	1	1	5
Gastroenteritis
subjects affected / exposed	1 / 6 (16.67%)	2 / 55 (3.64%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	2	0	1
Genital herpes
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Helicobacter infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Herpes simplex
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Herpes zoster
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Influenza
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Localised infection
subjects affected / exposed	0 / 6 (0.00%)	4 / 55 (7.27%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	4	0	0
Lymphangitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Nasopharyngitis
subjects affected / exposed	1 / 6 (16.67%)	10 / 55 (18.18%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	2	11	0	1
Oral herpes
subjects affected / exposed	0 / 6 (0.00%)	5 / 55 (9.09%)	0 / 10 (0.00%)	3 / 17 (17.65%)
occurrences all number	0	6	0	3
Oral infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Pharyngitis
subjects affected / exposed	1 / 6 (16.67%)	4 / 55 (7.27%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	6	0	1
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Rhinitis
subjects affected / exposed	3 / 6 (50.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	5 / 17 (29.41%)
occurrences all number	4	1	0	7
Sinusitis
subjects affected / exposed	1 / 6 (16.67%)	1 / 55 (1.82%)	0 / 10 (0.00%)	3 / 17 (17.65%)
occurrences all number	1	1	0	3
Skin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Subcutaneous abscess
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Tonsillitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	0	2
Tooth abscess
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Tooth infection
subjects affected / exposed	1 / 6 (16.67%)	2 / 55 (3.64%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	2	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 6 (16.67%)	4 / 55 (7.27%)	0 / 10 (0.00%)	2 / 17 (11.76%)
occurrences all number	1	7	0	3
Urinary tract infection
subjects affected / exposed	1 / 6 (16.67%)	10 / 55 (18.18%)	1 / 10 (10.00%)	3 / 17 (17.65%)
occurrences all number	1	11	2	3
Vaginal infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Viral infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	1	0	1	0
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Wound infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1
Metabolism and nutrition disorders
Cell death
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	2
Decreased appetite
subjects affected / exposed	2 / 6 (33.33%)	10 / 55 (18.18%)	3 / 10 (30.00%)	7 / 17 (41.18%)
occurrences all number	4	13	3	7
Diabetes mellitus
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	2	0	1
Dyslipidaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 55 (0.00%)	0 / 10 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0
Electrolyte imbalance
subjects affected / exposed	0 / 6 (0.00%)	0 / 55 (0.00%)	1 / 10 (10.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0
Hypercholesterolaemia
subjects affected / exposed	0 / 6 (0.00%)	3 / 55 (5.45%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	4	1	1
Hyperglycaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	2
Hypertriglyceridaemia
subjects affected / exposed	0 / 6 (0.00%)	2 / 55 (3.64%)	1 / 10 (10.00%)	1 / 17 (5.88%)
occurrences all number	0	3	1	1
Hypoalbuminaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	1
Hypocalcaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	2
Hypokalaemia
subjects affected / exposed	1 / 6 (16.67%)	7 / 55 (12.73%)	1 / 10 (10.00%)	2 / 17 (11.76%)
occurrences all number	1	12	7	3
Hyponatraemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 55 (1.82%)	1 / 10 (10.00%)	2 / 17 (11.76%)
occurrences all number	0	1	1	3
Hypophosphataemia
subjects affected / exposed	0 / 6 (0.00%)	4 / 55 (7.27%)	0 / 10 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	4	0	1

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Were there any global substantial amendments to the protocol? Yes

15 Feb 2007

The PK sampling for paclitaxel was changed based on data from the [CRAD001C2104] study.No statistically significant interaction could be shown between the two drugs for Tmax, Cmax and AUClast. In the present study, everolimus could have been administered once-weekly at doses ranging from 30 mg to 50 mg and if feasible, as high as 70 mg. Potential for the effect of everolimus on paclitaxel at higher doses could not be excluded. It was decided that a full paclitaxel pharmacokinetic profile, assessed in a subset of patients receiving the drug combination, would best address the objective to assess the effect of everolimus on systemic plasma exposure of paclitaxel. The collection of trough plasma concentrations of paclitaxel in the present study was removed from the protocol and paclitaxel pharmacokinetic profile assessment at higher dose levels of everolimus was added. Paclitaxel samples were to be collected in at least four patients.Clarifications regarding the washout period for endocrine treatment and lapatinib received prior to study start were added to the exclusion criteria. Inclusion/Exclusion criteria regarding previous taxane therapy for advanced disease were adapted to reflect current treatment practice. Slight changes to blood collection for analysis procedures were made. Novartis RECIST guideline was replaced by: Guidelines for Response, Duration of Overall Response, Time to Treatment Failure (TTF), Time to Progression (TTP), Progression-Free Survival and Overall Survival (based on RECIST).

11 Mar 2008

A phase II component was added to the study to evaluate the efficacy of the recommended dose levels/regimens of everolimus with trastuzumab and paclitaxel therapy as determined in the phase I part of the trial. Some other changes were: •Some clarifications, as well as changes to improve consistency, were made to dose modifications due to AEs. •The use of any paclitaxel provided by any manufacturer, instead of only Taxol®, was permitted, where applicable, considering local regulations and practices. •Unscheduled pharmacokinetic sampling; on the day of scheduled PK sampling the dose of the relevant study drug was missed, was clarified. •Pharmacokinetic parameters determined from plasma concentration-time profiles were added or clarified. •An additional sampling time point for plasma markers of angiogenesis (VEGF, bFGF) were added at the EOT visit.

14 Aug 2009

Enrollment was closed on 31 October 2008; 33 patients were enrolled and treated (6 patients in the 5 mg daily schedule, 17 patients in the 10 mg daily schedule and 10 patients in the 30 mg weekly schedule). From the last dose decision teleconference (31-Sept-2008), the study team and investigators concluded that 10 mg daily dose of everolimus in combination with trastuzumab and paclitaxel presented the most favorable risk/benefit profile for this patient population and therefore would be evaluated in the phase II part of the study: everolimus 10 mg daily in combination with trastuzumab and paclitaxel.

07 May 2010

Reactivation of hepatitis B (HBV) was observed in patients with cancer receiving chemotherapy (Yeo 2004). Sporadic cases of hepatitis B reactivation have also been seen in this setting with everolimus. Use of antivirals during anti-cancer therapy has been shown to reduce the risk of hepatitis B virus reactivation and associated morbidity and mortality (Loomba et al 2008). Guidance was added regarding the identification of patients at risk of hepatitis B, providing prophylactic treatment to them prior to and throughout the duration of everolimus therapy, and monitoring them for reactivation of HBV. Guidance on the management of patients at risk of hepatitis C viral reactivation was also provided.

25 Mar 2013

Redefine the follow-up survival period for Phase II. Per the original definition, patients are to be followed for survival every 3 months until death or lost to follow-up, up to 3 years after last patient’s EOT (i.e. last patient’s last date of study treatment) whichever is later. Per this amendment, patients will be followed for survival up to 3 years after last patient’s first visit. This newly defined follow-up period when implemented will shorten the follow-up period by approximately 2 years and will only apply to 9 patients or less who are being followed at that time.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A phase Ib/II study investigating the combination of everolimus with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer

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Subject disposition

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Baseline characteristics

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End points

Primary: Overall Response Rate: RAD001 10 mg + PT, Daily (Phase 2)

Primary: Overall Response Rate: RAD001 10 mg + PT, Daily (Phase 2)

Secondary: Best Overall Response

Secondary: Best Overall Response

Secondary: Progression Free Survival (PFS): RAD001 10 mg + PT, Daily (Phase 2)

Secondary: Progression Free Survival (PFS): RAD001 10 mg + PT, Daily (Phase 2)

Secondary: Overall Survival (OS): RAD001 10 mg + PT, Daily (Phase 2)

Secondary: Overall Survival (OS): RAD001 10 mg + PT, Daily (Phase 2)

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Clinical trials

Clinical Trial Results: A phase Ib/II study investigating the combination of everolimus with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall Response Rate: RAD001 10 mg + PT, Daily (Phase 2)

Primary: Overall Response Rate: RAD001 10 mg + PT, Daily (Phase 2)

Secondary: Best Overall Response

Secondary: Best Overall Response

Secondary: Progression Free Survival (PFS): RAD001 10 mg + PT, Daily (Phase 2)

Secondary: Progression Free Survival (PFS): RAD001 10 mg + PT, Daily (Phase 2)

Secondary: Overall Survival (OS): RAD001 10 mg + PT, Daily (Phase 2)

Secondary: Overall Survival (OS): RAD001 10 mg + PT, Daily (Phase 2)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A phase Ib/II study investigating the combination of everolimus with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer