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Clinical Trial Results:
Randomized crossover trial to assess the effects and quality of life in patients with locally advanced or metastatic pancreatic cancer treated with gemcitabine in combination with nab-paclitaxel: QOLINPAC

Summary
EudraCT number	2013-004101-75
Trial protocol	BE
Global end of trial date	29 Apr 2019

Results information
Results version number	v1(current)
This version publication date	08 Aug 2019
First version publication date	08 Aug 2019
Other versions
Summary report(s)	Consort diagram QOL analysis methodology Deaths on treatment Protocol deviations Selected references Publications Abbreviations

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

S56122-ML10190

ISRCTN number

US NCT number

NCT02106884

WHO universal trial number (UTN)

Other trial identifiers

Celgene internal number: AX-CL-PANC-PI-003568

Sponsor organisation name

UZ Leuven

Sponsor organisation address

Herestraat 49, Leuven, Belgium, 3000

Public contact

Prof. Dr. Eric Van Cutsem, UZ Leuven, Digestive oncology, 0032 16344225, eric.vancutsem@uzleuven.be

Scientific contact

Prof. Dr. Eric Van Cutsem, UZ Leuven, Digestive oncology, 0032 16344225, eric.vancutsem@uzleuven.be

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

29 Apr 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

29 Apr 2019

Global end of trial reached?

Yes

Global end of trial date

29 Apr 2019

Was the trial ended prematurely?

Main objective of the trial

To compare quality of life scores and times to definitive deterioration of the quality of life (QOL) scores in patients receiving nab-paclitaxel (n-P) + gemcitabine (G) versus gemcitabine (G) in monotherapy using the EORTC QLQ-C30 questionnaire.

Protection of trial subjects

Ethics review and approval, informed consent, prophylactic medication prior to infusions (to prevent chemotherapy known adverse events as per current practice and protocol recommendations), supportive care and routine monitoring.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 May 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy, Scientific research

Long term follow-up duration

3 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 146

Worldwide total number of subjects

146

EEA total number of subjects

146

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

One hundred fourty-six patients were included. First patient enrolled: 08-May-2014. Last patient enrolled: 25-Nov-2015. End of trial notification was dated 15-May-2018 (last patient last visit) and submitted to EC and CA 10-Jul-2018. Last follow-up (FU) data collected 05-Feb-2019. The cut off date for final data was on 29-Apr-2019.

Screening details

The study target population was represented by patients with metastatic or unresectable locally advanced pancreatic adenocarcinoma, histologically or cytologically confirmed, eligible for treatment with gemcitabine and nab-paclitaxel in a first line setting. Patients were screened as per inclusion and exclusion criteria per protocol.

Period 1 title

Full study duration: baseline to FU (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm A - nab-paclitaxel and gemcitabine

Arm description

Patients were randomised to receive a combination regimen of nab-paclitaxel and gemcitabine.

Arm type

Experimental

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

Other name

Abraxane

Pharmaceutical forms

Concentrate for suspension for injection

Routes of administration

Intravenous use

Dosage and administration details

Per protocol dose was 125 mg/m2. Schedule: Infusions repeated for three weeks followed by a week of rest (4 week cycles). Nab-paclitaxel infusions were planned every 7 days on the same day of the week; deviations more than 2 days were not allowed.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Gemzar

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Per protocol dose: 1000 mg/m2. Schedule: For patients in Arm A, gemcitabine was given the same day with and following nab-paclitaxel, i.e. once weekly for 3 weeks followed by a week of rest then repeat (4 week cycles). Gemcitabine infusions were planned every 7 days on the same day of the week; deviations more than 2 days were not allowed.

Arm B - gemcitabine monotherapy

Arm description

Patients randomised to receive gemcitabine monotherapy.

Arm type

Standard of care - no comparator

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Gemzar

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Per protocol dose: 1000 mg/m2. Schedule: For patients in Arm B, gemcitabine was given in an initial sequence of seven weeks followed by a week of rest (first cycle is 8 weeks) then every week for three weeks followed by a week of rest (cycle 2 and subsequent cycles are of 4 weeks). Gemcitabine infusions were planned every 7 days on the same day of the week; deviations more than 2 days were not allowed. Patients in Arm B progressing on gemcitabine monotherapy and eligible to receive nab-paclitaxel and gemcitabine were allowed to switch to the combination.

Number of subjects in period 1	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy
Started	72	74
Completed	72	73
Not completed	0	1
Change of diagnosis/exclusion criterion	-	1

Baseline characteristics

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Reporting group title

Arm A - nab-paclitaxel and gemcitabine

Reporting group description

Patients were randomised to receive a combination regimen of nab-paclitaxel and gemcitabine.

Reporting group title

Arm B - gemcitabine monotherapy

Reporting group description

Patients randomised to receive gemcitabine monotherapy.

Reporting group values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Total
Number of subjects	72	74	146
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	39	37	76
From 65-84 years	33	37	70
85 years and over	0	0	0
Gender categorical
Units: Subjects
Female	31	32	63
Male	41	42	83
ECOG performance status
WHO EGOG performance status (PS) scale 0 Able to carry out all normal activity without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out light work 2 Ambulatory and capable of all self-care but unable to carry out any work; up and about more than 50% of waking hours. 3 Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair
Units: Subjects
PS = 0	27	23	50
PS = 1	42	49	91
PS = 2	3	2	5
Site of pancreatic tumour
Units: Subjects
Head	16	19	35
Body	37	34	71
Tail	19	21	40
Locally advanced / metastatic
Units: Subjects
Locally advanced	10	11	21
Metastatic	62	63	125
Adjuvant treatment prior to inclusion
Units: Subjects
Yes	5	6	11
No	67	68	135

Subject analysis set title

Intent to treat set (ITT)

Subject analysis set type

Intention-to-treat

Subject analysis set description

All patients who consented to participate in the study and fulfilled all inclusion/exclusion criteria. One patient initially treated for pancreatic adenocarcinoma was excluded from the ITT set due to a subsequent change in diagnosis (neuroendocrine tumour).

Subject analysis set title

Safety set

Subject analysis set type

Safety analysis

Subject analysis set description

All patients treated on trial (at least one dose of treatment).

Subject analysis sets values	Intent to treat set (ITT)	Safety set
Number of subjects	145	146
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	76	76
From 65-84 years	69	70
85 years and over	0	0
Age continuous
Units:
	±	±
Gender categorical
Units: Subjects
Female	63	63
Male	82	83
ECOG performance status
WHO EGOG performance status (PS) scale 0 Able to carry out all normal activity without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out light work 2 Ambulatory and capable of all self-care but unable to carry out any work; up and about more than 50% of waking hours. 3 Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair
Units: Subjects
PS = 0	50	50
PS = 1	90	91
PS = 2	5	5
Site of pancreatic tumour
Units: Subjects
Head	34	35
Body	71	71
Tail	40	40
Locally advanced / metastatic
Units: Subjects
Locally advanced	20	21
Metastatic	125	125
Adjuvant treatment prior to inclusion
Units: Subjects
Yes	11	11
No	134	135

End points

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Reporting group title

Arm A - nab-paclitaxel and gemcitabine

Reporting group description

Patients were randomised to receive a combination regimen of nab-paclitaxel and gemcitabine.

Reporting group title

Arm B - gemcitabine monotherapy

Reporting group description

Patients randomised to receive gemcitabine monotherapy.

Subject analysis set title

Intent to treat set (ITT)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Safety set

Subject analysis set type

Safety analysis

Subject analysis set description

All patients treated on trial (at least one dose of treatment).

Primary: Deterioration-free survival rate of the QOL global health status at 3, 6 and 12 months

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End point title

Deterioration-free survival rate of the QOL global health status at 3, 6 and 12 months

End point description

1474 QOL questionnaires were completed (714 in arm A; 761 in arm B) The QOL global health status (GHS) is a functional parameter derived from the EORTC QLQ - C30 questionnaire, based on questions 29 "How would you rate your overall health during the past week?" and 30 "How would you rate your overall quality of life during the past week?". The deterioration free survival rate at 3 months is defined as the Kaplan-Meier estimate of the probability of being alive and free of deterioration of the QOL score at 3 months. The definitive deterioration of the QOL score is a decrease of at least 10 points (minimal clinical important difference) as compared to the baseline score, with no further improvement of more than 10 points as compared to the score qualifying the deterioration or with no data after the deterioration was observed. Death was also considered as an event if the patient did not experience deterioration before death. Patients without event were censored at the time of last FU.

End point type

Primary

End point timeframe

From date of randomisation to 3, 6 and 12 months respectively

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Percentage
Rate at 3 months	89	73	81
Rate at 6 months	74	59	66
Rate at 12 months	40	35	38

Attachments

GHS - TUDD

Difference in GHS deterioration-free rates 3 mo

Statistical analysis description

Comparison of the deterioration-free survival rates based on definitive deterioration or death at 3, 6, 9, 12 months after randomisation. The comparisons are based on Z-tests after log-log transformations of the survival estimates. Deterioration-free survival rates at 3 months were respectively: Arm A (n-P+G) 88.89%, 95%CI [79.0-94.3] and Arm B (G monotherapy) 79.74%, 95%CI [60.7-81.3] with p=0.0166. Additional data is available upon request.

Comparison groups

Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.0166 ^[2]

Method

Z-test

Confidence interval

Notes
[1] - The difference in the deterioration-free rate of the GHS at 3 months between the two arms was statistically significant.
[2] - A stratification per centre was performed. 95% confidence intervals were based on a non-parametric bootstrap procedure. The difference was still significant with p<0.05.

Primary: QOL global health status deterioration-free median survival

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End point title

QOL global health status deterioration-free median survival

End point description

The deterioration-free survival is defined as the Kaplan-Meier estimate of median survival time to definitive deterioration of the QOL score or death. The definitive deterioration of the QOL score is a decrease of at least 10 points (minimal clinical important difference) as compared to the baseline score, with no further improvement of more than 10 points as compared to the score qualifying the deterioration or with no data after the deterioration was observed. Death was also considered as an event if the patient did not experience deterioration before death. Patients without event were censored at the time of last follow-up.

End point type

Primary

End point timeframe

From date of randomisation to end of follow up (max 3 years after database lock when applicable).

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Months
median (confidence interval 95%)	10.04 (7.16 to 12.02)	8.02 (5.49 to 11.37)	8.74 (6.67 to 10.84)

Deterioration-free survival time Kaplan-Meier

Statistical analysis description

The deterioration-free survival is defined as the Kaplan-Meier estimate of median survival time to definitive deterioration of the QOL score (as defined above) or death. Median times to definitive deterioration or death with 95%CI are presented for the GHS QOL score per arm. A logrank comparison between arms was performed and the p-value is provided below. Additional data is available upon request.

Comparison groups

Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

= 0.378 ^[4]

Method

Logrank

Confidence interval

Notes
[3] - Kaplan-Meier.
[4] - The difference between arms of the median times to definitive deterioration of the GHS was not statistically significant.

Secondary: Deterioration-free survival rate of the QOL functional scales at 3, 6 and 12 months

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End point title

Deterioration-free survival rate of the QOL functional scales at 3, 6 and 12 months

End point description

The QOL functional scales are derived from the EORTC QLQ - C30: Physical functioning (PF2)Q 1-5, Role functioning (RF2) Q6&7, Emotional functioning (EF) Q21-24, Cognitive functioning (CF) Q20&25, Social functioning (SF) Q26&27. The deterioration free survival rate at 3 months is defined as the Kaplan-Meier estimate of the probability of being alive and free of deterioration of the QOL score at 3 months. The definitive deterioration of the QOL score is a decrease of at least 10 points (minimal clinical important difference) as compared to the baseline score, with no further improvement of more than 10 points as compared to the score qualifying the deterioration or with no data after the deterioration was observed. Death was also considered as an event if the patient did not experience deterioration before death. Patients without event were censored at the time of last follow-up.

End point type

Secondary

End point timeframe

From date of randomisation to 3, 6 and 12 months respectively

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Percentage
Physical functioning 3 months	76	67	72
Physical functioning 6 months	65	57	61
Physical functioning 12 months	32	31	31
Role functioning 3 months	81	68	74
Role functioning 6 months	67	53	60
Role functioning 12 months	36	32	34
Emotional functioning 3 months	93	79	86
Emotional functioning 6 months	79	68	74
Emotional functioning 12 months	40	43	42
Cognitive functioning 3 months	89	78	83
Cognitive functioning 6 months	75	66	70
Cognitive functioning 12 months	40	45	42
Social functioning 3 months	86	75	81
Social functioning 6 months	69	64	67
Social functioning 12 months	36	42	39

Difference in QOL deterioration-free rates at 3 mo

Statistical analysis description

Comparison of the deterioration-free survival rates of the QOL functional scales based on definitive deterioration or death at 3, 6, 9, 12 months after randomisation. The comparisons are based on Z-tests after log-log transformations of the survival estimates. Deterioration-free survival rates at 3 months difference between arms was significant for the Emotional functioning scale: Arm A (n-P+G) 93.1%, 95%CI [84.1-97.0] and Arm B (G monotherapy) 79.3%, 95%CI [68.1-87.0] with p=0.0238.

Comparison groups

Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.0238 ^[6]

Method

z-test

Confidence interval

Notes
[5] - The difference in the deterioration-free rate at 3 months between the two arms was statistically significant for Emotional functioning. Additional data available upon request.
[6] - Significant for Emotional functioning.

Secondary: QOL functional scales deterioration-free median survival

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End point title

QOL functional scales deterioration-free median survival

End point description

End point type

Secondary

End point timeframe

From date of randomisation to end of follow up (max 3 years after database lock when applicable).

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Months
median (confidence interval 95%)
Physical functioning	7.85 (6.51 to 10.38)	6.64 (4.17 to 9.33)	7.82 (6.31 to 9.07)
Role functioning	7.97 (6.51 to 10.58)	6.51 (4.40 to 10.18)	7.82 (6.11 to 9.00)
Emotional functioning	10.04 (8.25 to 12.02)	11.04 (8.02 to 12.48)	10.38 (8.74 to 11.96)
Cognitive functioning	8.87 (7.16 to 12.35)	11.37 (6.64 to 12.55)	9.92 (7.89 to 12.12)
Social functioning	9.05 (6.90 to 11.27)	9.20 (6.11 to 12.48)	9.13 (7.59 to 11.37)

Deterioration-free survival time Kaplan-Meier

Statistical analysis description

The deterioration-free survival is defined as the Kaplan-Meier estimate of median survival time to definitive deterioration of the QOL score (as defined above) or death. Median times to definitive deterioration or death with 95%CI are presented for the functional QOL scales per arm. A logrank comparison between arms was performed for each scale. None of the comparisons was statistically significant. Additional data is available upon request.

Comparison groups

Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

= 0.8408 ^[8]

Method

Logrank

Confidence interval

Notes
[7] - Kaplan-Meier.
[8] - p-value of the inter-arm comparison of the median deterioration-free survival times for Physical functioning is provided. None of the comparisons of the Functional scales were statistically significant. Additional data is available upon request.

Secondary: Deterioration-free survival rate of the QOL symptom scales at 3, 6 and 12 months

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End point title

Deterioration-free survival rate of the QOL symptom scales at 3, 6 and 12 months

End point description

The QOL symptom scales are derived from the EORTC QLQ - C30: Fatigue (FA) Q 10&12&18, Nausea and vomiting (NV) Q14&15, Pain (PA) Q9&19, Dyspnoea(DY) Q8, Insomnia (SL) Q11, Appetite loss (AP) Q13, Constipation (CO) Q16, Diarrhoea (DI) Q17, Financial difficulties (FI) Q28. The deterioration free survival rate at 3 months is defined as the Kaplan-Meier estimate of the probability of being alive and free of deterioration of the QOL score at 3 months. The definitive deterioration of the QOL score is a decrease of at least 10 points (minimal clinical important difference) as compared to the baseline score, with no further improvement of more than 10 points as compared to the score qualifying the deterioration or with no data after the deterioration was observed. Death was also considered as an event if the patient did not experience deterioration before death. Patients without event were censored at the time of last follow-up.

End point type

Secondary

End point timeframe

From date of randomisation to 3, 6 and 12 months respectively

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Percentage
Fatigue 3 months	92	79	85
Fatigue 6 months	76	70	73
Fatigue 12 months	47	45	46
Nausea and vomiting 3 months	88	75	81
Nausea and vomiting 6 months	75	63	69
Nausea and vomiting 12 months	44	45	44
Pain 3 months	85	71	78
Pain 6 months	76	64	70
Pain 12 months	39	40	40
Dyspnoea 3 months	89	75	82
Dyspnoea 6 months	74	67	70
Dyspnoea 12 months	43	47	45
Insomnia 3 months	75	74	74
Insomnia 6 months	60	61	61
Insomnia 12 months	38	39	38
Appetite loss 3 months	82	70	76
Appetite loss 6 months	64	56	60
Appetite loss 12 months	39	35	37
Constipation 3 months	82	74	78
Constipation 6 months	68	63	65
Constipation 12 months	33	38	35
Diarrhoea 3 months	88	77	82
Diarrhoea 6 months	72	66	69
Diarrhoea 12 months	38	32	40
Financial difficulties 3 months	92	79	85
Financial difficulties 6 months	78	71	74
Financial difficulties 12 months	43	47	45

Difference in QOL deterioration-free rates at 3 mo

Statistical analysis description

Comparison of the deterioration-free survival rates of the QOL symptom scales based on definitive deterioration or death at 3, 6, 9, 12 months after randomisation. The comparisons are based on Z-tests after log-log transformations of the survival estimates. Deterioration-free survival rates at 3 months differences between arms were significant for Fatigue p=0.0433, Dyspnoea p=0.0381 and Financial difficulties p=0.0433. Additional data is available upon request.

Comparison groups

Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

^[9]

P-value

= 0.0433 ^[10]

Method

z-test

Confidence interval

Notes
[9] - Significant for Fatigue, Dyspnoea, Financial difficulties.
[10] - p-value provided for Fatigue. Additional data available upon request.

Secondary: QOL symptom scales deterioration-free median survival

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End point title

QOL symptom scales deterioration-free median survival

End point description

End point type

Secondary

End point timeframe

From date of randomisation to end of follow up (max 3 years after database lock when applicable).

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Months
median (confidence interval 95%)
Fatigue	10.60 (8.25 to 14.55)	11.04 (8.44 to 13.17)	10.87 (8.97 to 12.71)
Nausea and vomiting	10.48 (8.97 to 14.55)	10.87 (6.01 to 13.21)	10.58 (8.64 to 12.35)
Pain	9.05 (6.97 to 11.27)	9.72 (6.44 to 13.17)	9.20 (7.82 to 11.37)
Dyspnoea	10.27 (7.59 to 12.88)	11.43 (6.51 to 13.86)	10.58 (8.25 to 12.48)
Insomnia	7.82 (5.55 to 10.61)	8.97 (5.62 to 12.29)	8.74 (6.28 to 10.61)
Appetite loss	8.44 (6.28 to 11.27)	8.44 (4.63 to 11.37)	8.44 (6.18 to 10.58)
Constipation	8.43 (6.51 to 10.38)	9.17 (6.11 to 11.73)	8.97 (6.90 to 10.58)
Diarrhoea	8.99 (7.66 to 11.04)	9.20 (6.51 to 13.17)	9.10 (7.85 to 11.04)
Financial difficulties	10.27 (7.66 to 12.35)	11.43 (8.71 to 13.44)	10.61 (8.71 to 12.35)

Deterioration-free survival time Kaplan-Meier

Statistical analysis description

The deterioration-free survival is defined as the Kaplan-Meier estimate of median survival time to definitive deterioration of the QOL score (as defined above) or death. Median times to definitive deterioration or death with 95%CI are presented for the QOL symptom scales per arm. A logrank comparison between arms was performed for each scale. None of the comparisons was statistically significant. Additional data is available upon request.

Comparison groups

Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other ^[11]

P-value

= 0.5448 ^[12]

Method

Logrank

Confidence interval

Notes
[11] - Kaplan-Meier survival analysis.
[12] - p-value of the inter-arm comparison of the median deterioration-free survival times for Fatigue is provided. None of the comparisons of the Symptom scales were statistically significant. Additional data is available upon request.

Secondary: Exposure to treatment

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End point title

Exposure to treatment

End point description

Total cumulative dose exposure is measured by dose intensity (total dose given/total dose planned*100) per drug. The "planned dose of nab-paclitaxel" refers, as per protocol, to a weekly administration of 125 mg/m² nab-paclitaxel for 3 weeks followed by a week of rest in 4-week cycles (Arm A only). The "planned dose of gemcitabine” refers to a weekly administration of 1000 mg/m2 gemcitabine following the same day nab-paclitaxel dose in Arm A (4-week cycles) and standard in Arm B (7 infusions + 1 week of rest for cycle 1 and 4-week cycles afterwards). Total doses are the sums of all theoretical "planned" and given doses, respectively.

End point type

Secondary

End point timeframe

From date of first infusion to date of last infusion. For patients in arm B who switched to the combination of n-P + G in second line dose exposure to n-P is given for this subset.

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Safety set
Number of subjects analysed	72	74	146 ^[13]
Units: Percentage
Nab-paclitaxel	73	74	74
Gemcitabine	75	70	72

Notes
[13] - All patients received at least one dose of treatment (Safety set).

No statistical analyses for this end point

Secondary: Overall response

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End point title

Overall response

End point description

Tumour response was assessed locally based on radiological assessments (CT/MRI) of target and non-target lesions and considering the occurrence of new lesions, as per RECIST criteria. Tumour response was defined at each evaluation as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). Best response during treatment was selected for each patient. Overall response (OR) is defined as the best tumor response on treatment for each patient. Responders were considered CR + PR. Some patients were not evaluable for response (no scans available). Overall response rates (ORR) were calculated based on the ITT set.

End point type

Secondary

End point timeframe

Duration of treatment

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Counts of participants
CR + PR	31	16	47
SD or PD	39	53	92
Not evaluable	2	4	6

Overall response counts and rates

Statistical analysis description

Descriptive. Rates of overall response (CR and PR) with 95%CI were calculated per arm: Arm A: ORR 44% 95%CI [32-56]; Arm B: ORR 23% 95%CI [13-33]. Percentages are based on evaluable patients only. A comparison between arms was performed (t-test) and the difference in response rates was statistically significant (p=0.008).

Comparison groups

Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other ^[14]

P-value

= 0.008 ^[15]

Method

t-test, 2-sided

Confidence interval

Notes
[14] - T-test double sided.
[15] - Difference between the 2 arms was statistically significant.

Secondary: Duration of response (in responders)

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End point title

Duration of response (in responders)

End point description

Duration of response was calculated from the date of first documented response to the date of progression (including SD after PR) or date of start of new treatment in not progressed, when available. In 2 patients with CR, periods of PR are included. For those not documented as progressed before death, an unknown duration was kept and considered missing data.

End point type

Secondary

End point timeframe

Treatment

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	29 ^[16]	15 ^[17]	44
Units: Months
median (full range (min-max))	6.3 (1.92 to 35)	7.4 (1.50 to 20)	6.83 (1.50 to 35)

Notes
[16] - 2 of 31 responders had an unknown duration of response thus not considered in this analysis
[17] - 1 of 16 responders had an unknown duration of response thus not considered in this analysis

No statistical analyses for this end point

Secondary: Disease control

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End point title

Disease control

End point description

Tumour response was assessed locally based on radiological assessments (CT/MRI) of target and non-target lesions and considering the occurrence of new lesions, as per RECIST criteria. Tumour response was defined at each evaluation as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). Best response during treatment was selected for each patient. Overall response is defined as the best tumor response on treatment for each patient. Disease control is defined as a best response on treatment of either CR, PR or SD (CR + PR + SD). Some patients were not evaluable for response (no scans available). Overall response rates were calculated based on the ITT set.

End point type

Secondary

End point timeframe

Duration of treatment

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Counts of participants
CR + PR + SD	58	60	118
PD	12	9	21
Not evaluable	2	4	6

Disease control counts and rates

Statistical analysis description

Descriptive. Rates of disease control (CR, PR and SD) with 95%CI were calculated per arm: Arm A: DC rate 83% 95%CI [74-92]; Arm B: OR rate 87% 95%CI [79-95]. Percentages are based on evaluable patients only. A comparison between arms was performed (t-test) and the difference in response rates was statistically significant (p=0.503).

Comparison groups

Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

= 0.503 ^[19]

Method

t-test, 2-sided

Confidence interval

Notes
[18] - T-test double sided
[19] - Not statistically significant

Secondary: Progression rates at 1 year

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End point title

Progression rates at 1 year

End point description

Rate of progression of disease occuring within 1 year from date of randomisation are listed per arm. Details are provided in attached documents.

End point type

Secondary

End point timeframe

1 year from date of randomisation

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Percentage
Progressed at 1 year	71	79	75
Not progressed at 1 year	29	21	25

No statistical analyses for this end point

Secondary: Progression free survival

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End point title

Progression free survival

End point description

Progression free survival time was considered from start of treatment until the first observation of disease progression or death from any cause, whichever occurred first. All patients (ITT).

End point type

Secondary

End point timeframe

Treatment + follow-up

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Months
median (confidence interval 95%)	7.01 (5.45 to 8.05)	5.06 (3.52 to 7.00)	5.85 (5.06 to 7.13)

Progression free survival median time Kaplan-Meier

Statistical analysis description

The median progression free survival is defined as the Kaplan-Meier estimate of median time from randomisation to first documented progression, date of last follow-up for non progressed patients or death. Median times with 95%CI are presented per arm. A logrank comparison between arms was performed and the P value is provided below. Additional data is available upon request.

Comparison groups

Arm B - gemcitabine monotherapy v Arm A - nab-paclitaxel and gemcitabine

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other ^[20]

P-value

= 0.0295 ^[21]

Method

Logrank

Confidence interval

Notes
[20] - Kaplan-Meier
[21] - The difference between arms of the progression free survival time was statistically significant.

Secondary: Death rates at 30 days from last treatment

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End point title

Death rates at 30 days from last treatment

End point description

Deaths of all causes occuring between the signature of consent and the date of last infusion + 30 days for each patient are listed per arm. Only one of these fatalities was deemed possibly related to the investigational drug. Details are provided in attached documents.

End point type

Secondary

End point timeframe

From signature of informed consent to last infusion + 30 days for each patient

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Percentage
Deceased at 30 days from last treatment	7	15	11
Alive at 30 days from last treatment	93	85	89

No statistical analyses for this end point

Secondary: Death rates at 1 year

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End point title

Death rates at 1 year

End point description

Rate of deaths of all causes occuring within 1 year from date of randomisation are listed per arm. Details are provided in attached documents.

End point type

Secondary

End point timeframe

1 year from the date of randomisation

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Percentage
Deceased at 1 year	51	51	51
Alive at 1 year	49	49	49

No statistical analyses for this end point

Secondary: Overall survival

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End point title

Overall survival

End point description

Overall survival was considered from start of treatment to death. All patients (ITT)

End point type

Secondary

End point timeframe

Treatment + follow-up

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Intent to treat set (ITT)
Number of subjects analysed	72	73	145
Units: Months
median (confidence interval 95%)	10.94 (8.97 to 15.18)	11.73 (8.74 to 13.44)	11.43 (9.13 to 13.21)

Overall survival median time Kaplan-Meier

Statistical analysis description

The median overall survival is defined as the Kaplan-Meier estimate of median time from randomisation to death or last follow-up. Median times to death with 95%CI are presented per arm. A logrank comparison between arms was performed and the P value is provided below. Additional data is available upon request.

Comparison groups

Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other ^[22]

P-value

= 0.7005 ^[23]

Method

Logrank

Confidence interval

Notes
[22] - Kaplan-Meier
[23] - The difference between arms of the median survival time was not statistically significant.

Secondary: Laboratory safety assessment

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End point title

Laboratory safety assessment

End point description

Severe laboratory abnormalities (hematology and biochemistry grade 3 and higher). Worst grade per patient. All patients treated (Safety set).

End point type

Secondary

End point timeframe

From signature of informed consent to end of treatment visit plus 30 days.

End point values	Arm A - nab-paclitaxel and gemcitabine	Arm B - gemcitabine monotherapy	Safety set
Number of subjects analysed	72	74 ^[24]	146
Units: Counts of participants
Hemoglobin decreased	10	8	18
Neutrophils decreased	31	31	62
White blood cell count decreased	22	11	33
Platelet count decreased	12	11	23
Hyperglycemia	6	10	16
Serum creatinine increased	0	2	2
Bilirubin increased	3	8	11
ALT increased	13	8	21
AST increased	7	8	15
ALP increased	9	11	20
Albumin decreased	4	4	8
Magnesium decreased	4	9	13
Sodium decreased	8	13	21
Potassium decreased	8	6	14
Potassium increased	1	0	1
Calcium decreased	3	2	5

Notes
[24] - Safety set - all patients.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Serious adverse events (SAE) and adverse events (AE) occurring from the signature of informed consent to the end of treatment visit plus 30 days.

Adverse event reporting additional description

All SAEs occurring between the signature of informed consent and the end of treatment visit + 30 days are listed. Severe adverse events (grade 3-5, worst grade per patient) are listed in the non-serious AE table, SAEs are included. A summary of the severe laboratory abnormalities is provided in section "End points".

Assessment type

Systematic

Dictionary name

NCI -CTCAE

Dictionary version

Reporting group title

Arm A - nab-paclitaxel and gemcitabine

Reporting group description

Patients were randomised to receive a combination regimen of nab-paclitaxel and gemcitabine

Reporting group title

ARM B - gemcitabine monotherapy

Reporting group description

Patients randomised to receive gemcitabine in monotherapy. Some patients within this Arm switched to the combination regimen and received nab-paclitaxel with gemcitabine after the first progression on gemcitabine monotherapy. Safety set. All patients included.

Reporting group title

Total (Safety set)

Reporting group description

Safety set. All patients included. ??? 16 deaths on trt due to all causes within 30 days from last trt ----->>> this entered here

Reporting group title

Subset nab-paclitaxel + gemcitabine in 2nd line

Reporting group description

A separate additional analysis is performed for the population subset that received the combination of nab-paclitaxel and gemcitabine in second line, after the initial progression on gemcitabine monotherapy (cross-over group).

Serious adverse events	Arm A - nab-paclitaxel and gemcitabine	ARM B - gemcitabine monotherapy	Total (Safety set)	Subset nab-paclitaxel + gemcitabine in 2nd line
Total subjects affected by serious adverse events
subjects affected / exposed	50 / 72 (69.44%)	48 / 74 (64.86%)	98 / 146 (67.12%)	15 / 37 (40.54%)
number of deaths (all causes)	5	11	16	4
number of deaths resulting from adverse events	2	3	5	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain
subjects affected / exposed	0 / 72 (0.00%)	2 / 74 (2.70%)	2 / 146 (1.37%)	2 / 37 (5.41%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Thromboembolic event
subjects affected / exposed	3 / 72 (4.17%)	4 / 74 (5.41%)	7 / 146 (4.79%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 6	0 / 3	1 / 9	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 0
General disorders and administration site conditions
Edema limbs
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Fatigue
subjects affected / exposed	3 / 72 (4.17%)	5 / 74 (6.76%)	8 / 146 (5.48%)	2 / 37 (5.41%)
occurrences causally related to treatment / all	2 / 3	3 / 5	5 / 8	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fever
subjects affected / exposed	9 / 72 (12.50%)	9 / 74 (12.16%)	18 / 146 (12.33%)	2 / 37 (5.41%)
occurrences causally related to treatment / all	7 / 10	3 / 10	10 / 20	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Flu like symptoms
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Malaise
subjects affected / exposed	3 / 72 (4.17%)	1 / 74 (1.35%)	4 / 146 (2.74%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	3 / 3	1 / 1	4 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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 / 1	0 / 1	0 / 0
Alteration of general condition
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug misuse
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Generalized edema
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Respiratory, thoracic and mediastinal disorders
Dyspnea
subjects affected / exposed	2 / 72 (2.78%)	0 / 74 (0.00%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemoptysis
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Pleural effusion
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary edema
subjects affected / exposed	0 / 72 (0.00%)	2 / 74 (2.70%)	2 / 146 (1.37%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusion
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Investigations
Neutrophil count decreased
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Fracture
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Cardiac disorders
Myocardial infarction
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Nervous system disorders
Ischemia cerebrovascular
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Tremor
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vasovagal reaction
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Blood and lymphatic system disorders
Anemia
subjects affected / exposed	2 / 72 (2.78%)	3 / 74 (4.05%)	5 / 146 (3.42%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 2	2 / 3	2 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemolytic Uremic Syndrome
subjects affected / exposed	3 / 72 (4.17%)	2 / 74 (2.70%)	5 / 146 (3.42%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	3 / 3	2 / 2	5 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombotic thrombocytopenic purpura
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	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 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 72 (1.39%)	4 / 74 (5.41%)	5 / 146 (3.42%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colonic perforation
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	2 / 72 (2.78%)	0 / 74 (0.00%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhea
subjects affected / exposed	2 / 72 (2.78%)	0 / 74 (0.00%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal and galbladder obstruction on stent
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal obstruction
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Gastric hemorrhage
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 72 (2.78%)	1 / 74 (1.35%)	3 / 146 (2.05%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastro-enteritis
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sigmoiditis
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic duct stenosis
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 72 (1.39%)	2 / 74 (2.70%)	3 / 146 (2.05%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	3 / 72 (4.17%)	1 / 74 (1.35%)	4 / 146 (2.74%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomach pain
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 72 (2.78%)	3 / 74 (4.05%)	5 / 146 (3.42%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 2	2 / 3	2 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stenosis
subjects affected / exposed	1 / 72 (1.39%)	3 / 74 (4.05%)	4 / 146 (2.74%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 72 (1.39%)	2 / 74 (2.70%)	3 / 146 (2.05%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Galbladder obstruction
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Cholangitis
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholestasis
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	2 / 72 (2.78%)	1 / 74 (1.35%)	3 / 146 (2.05%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 72 (0.00%)	3 / 74 (4.05%)	3 / 146 (2.05%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 4	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Back pain
subjects affected / exposed	3 / 72 (4.17%)	0 / 74 (0.00%)	3 / 146 (2.05%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal infection
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Biliary tract infection
subjects affected / exposed	3 / 72 (4.17%)	3 / 74 (4.05%)	6 / 146 (4.11%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	2 / 3	0 / 3	2 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder infection
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchial infection
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic infection
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	7 / 72 (9.72%)	2 / 74 (2.70%)	9 / 146 (6.16%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	3 / 9	1 / 2	4 / 11	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infectious syndrome with mastoiditis/synovitis/positive hemocultures
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic thromboflebitis
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (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
Sepsis
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
Urinary tract infection
subjects affected / exposed	4 / 72 (5.56%)	0 / 74 (0.00%)	4 / 146 (2.74%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	2 / 72 (2.78%)	3 / 74 (4.05%)	5 / 146 (3.42%)	2 / 37 (5.41%)
occurrences causally related to treatment / all	2 / 3	0 / 4	2 / 7	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Major denutrition
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Arm A - nab-paclitaxel and gemcitabine	ARM B - gemcitabine monotherapy	Total (Safety set)	Subset nab-paclitaxel + gemcitabine in 2nd line
Total subjects affected by non serious adverse events
subjects affected / exposed	72 / 72 (100.00%)	74 / 74 (100.00%)	146 / 146 (100.00%)	37 / 37 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Vascular disorders
Capillary leak syndrome
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
Hematoma
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
Hypertension
subjects affected / exposed	8 / 72 (11.11%)	7 / 74 (9.46%)	15 / 146 (10.27%)	1 / 37 (2.70%)
occurrences all number	12	11	23	1
Thromboembolic event
subjects affected / exposed	5 / 72 (6.94%)	6 / 74 (8.11%)	11 / 146 (7.53%)	0 / 37 (0.00%)
occurrences all number	6	8	14	0
Hypotension
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
General disorders and administration site conditions
Edema limbs
subjects affected / exposed	2 / 72 (2.78%)	1 / 74 (1.35%)	3 / 146 (2.05%)	1 / 37 (2.70%)
occurrences all number	2	1	3	1
Fatigue
subjects affected / exposed	16 / 72 (22.22%)	21 / 74 (28.38%)	37 / 146 (25.34%)	10 / 37 (27.03%)
occurrences all number	26	38	64	21
Fever
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Multi-organ failure
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
General status alteration
subjects affected / exposed	1 / 72 (1.39%)	3 / 74 (4.05%)	4 / 146 (2.74%)	1 / 37 (2.70%)
occurrences all number	1	3	4	1
Pain
subjects affected / exposed	1 / 72 (1.39%)	5 / 74 (6.76%)	6 / 146 (4.11%)	2 / 37 (5.41%)
occurrences all number	2	5	7	2
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Dyspnea
subjects affected / exposed	6 / 72 (8.33%)	4 / 74 (5.41%)	10 / 146 (6.85%)	0 / 37 (0.00%)
occurrences all number	9	5	14	0
Epistaxis
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	1 / 37 (2.70%)
occurrences all number	1	1	2	1
Hypoxia
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
COPD
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Pleural effusion
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences all number	1	1	2	0
Pumonary edema
subjects affected / exposed	0 / 72 (0.00%)	2 / 74 (2.70%)	2 / 146 (1.37%)	1 / 37 (2.70%)
occurrences all number	0	2	2	1
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 72 (0.00%)	2 / 74 (2.70%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences all number	0	2	2	0
Anxiety
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences all number	0	1	1	1
Depression
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Insomnia
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Investigations
Weight loss
subjects affected / exposed	2 / 72 (2.78%)	2 / 74 (2.70%)	4 / 146 (2.74%)	2 / 37 (5.41%)
occurrences all number	2	2	4	2
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
Myocardial infarction
subjects affected / exposed	0 / 72 (0.00%)	3 / 74 (4.05%)	3 / 146 (2.05%)	0 / 37 (0.00%)
occurrences all number	0	3	3	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
Hemiparesis
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
Peripheral motor neuropathy
subjects affected / exposed	2 / 72 (2.78%)	0 / 74 (0.00%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences all number	3	0	3	0
Peripheral sensory neuropathy
subjects affected / exposed	5 / 72 (6.94%)	2 / 74 (2.70%)	7 / 146 (4.79%)	2 / 37 (5.41%)
occurrences all number	6	3	9	3
Somnolence
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
Syncope
subjects affected / exposed	2 / 72 (2.78%)	3 / 74 (4.05%)	5 / 146 (3.42%)	1 / 37 (2.70%)
occurrences all number	2	3	5	1
Blood and lymphatic system disorders
Anemia
subjects affected / exposed	7 / 72 (9.72%)	11 / 74 (14.86%)	18 / 146 (12.33%)	2 / 37 (5.41%)
occurrences all number	9	18	27	2
Febrile neutropenia
subjects affected / exposed	3 / 72 (4.17%)	0 / 74 (0.00%)	3 / 146 (2.05%)	0 / 37 (0.00%)
occurrences all number	4	0	4	0
Hemolytic uremic syndrome
subjects affected / exposed	3 / 72 (4.17%)	3 / 74 (4.05%)	6 / 146 (4.11%)	0 / 37 (0.00%)
occurrences all number	3	3	6	0
Thrombotic thrombocytopenic purpura
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences all number	1	1	2	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 72 (4.17%)	8 / 74 (10.81%)	11 / 146 (7.53%)	2 / 37 (5.41%)
occurrences all number	5	9	14	2
Ascites
subjects affected / exposed	0 / 72 (0.00%)	2 / 74 (2.70%)	2 / 146 (1.37%)	1 / 37 (2.70%)
occurrences all number	0	2	2	1
Colitis
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	1 / 37 (2.70%)
occurrences all number	1	1	2	1
Colonic obstruction
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	2	2	0
Constipation
subjects affected / exposed	0 / 72 (0.00%)	2 / 74 (2.70%)	2 / 146 (1.37%)	1 / 37 (2.70%)
occurrences all number	0	2	2	1
Diarrhea
subjects affected / exposed	5 / 72 (6.94%)	2 / 74 (2.70%)	7 / 146 (4.79%)	2 / 37 (5.41%)
occurrences all number	5	2	7	2
Gastric ulcer
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences all number	0	1	1	1
Gastroparesis
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences all number	0	1	1	1
Gastrointestinal pain
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
Ileus
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Mucositis oral
subjects affected / exposed	2 / 72 (2.78%)	0 / 74 (0.00%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences all number	2	0	2	0
Nausea
subjects affected / exposed	5 / 72 (6.94%)	6 / 74 (8.11%)	11 / 146 (7.53%)	2 / 37 (5.41%)
occurrences all number	5	6	11	2
Obstruction gastric
subjects affected / exposed	2 / 72 (2.78%)	1 / 74 (1.35%)	3 / 146 (2.05%)	1 / 37 (2.70%)
occurrences all number	2	1	3	1
Diverticulitis
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences all number	0	1	1	1
Intrapancreatic obstruction
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences all number	0	1	1	1
Hematemesis
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Hernia inguinalis with obstruction
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Pancreatitis
subjects affected / exposed	1 / 72 (1.39%)	2 / 74 (2.70%)	3 / 146 (2.05%)	1 / 37 (2.70%)
occurrences all number	1	2	3	1
Small intestinal obstruction
subjects affected / exposed	2 / 72 (2.78%)	2 / 74 (2.70%)	4 / 146 (2.74%)	0 / 37 (0.00%)
occurrences all number	2	3	5	0
Stomach pain
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences all number	1	1	2	0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Vomiting
subjects affected / exposed	6 / 72 (8.33%)	4 / 74 (5.41%)	10 / 146 (6.85%)	0 / 37 (0.00%)
occurrences all number	6	4	10	0
Colonic perforation
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Hepatobiliary disorders
Bile duct stenosis
subjects affected / exposed	2 / 72 (2.78%)	6 / 74 (8.11%)	8 / 146 (5.48%)	1 / 37 (2.70%)
occurrences all number	2	6	8	1
Cholecystitis
subjects affected / exposed	1 / 72 (1.39%)	4 / 74 (5.41%)	5 / 146 (3.42%)	2 / 37 (5.41%)
occurrences all number	1	6	7	3
Gallbladder obstruction
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences all number	1	1	2	0
Hepatic failure
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences all number	1	1	2	0
Cholestasis
subjects affected / exposed	0 / 72 (0.00%)	2 / 74 (2.70%)	2 / 146 (1.37%)	1 / 37 (2.70%)
occurrences all number	0	3	3	1
Dilated bile ducts
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Jaundice
subjects affected / exposed	2 / 72 (2.78%)	0 / 74 (0.00%)	2 / 146 (1.37%)	0 / 37 (0.00%)
occurrences all number	2	0	2	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 72 (0.00%)	3 / 74 (4.05%)	3 / 146 (2.05%)	0 / 37 (0.00%)
occurrences all number	0	3	3	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences all number	0	1	1	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 72 (1.39%)	2 / 74 (2.70%)	3 / 146 (2.05%)	1 / 37 (2.70%)
occurrences all number	1	2	3	1
Bone pain
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
Myalgia
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	2	0	2	0
Pain in extremity
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
Infections and infestations
Abdominal infection
subjects affected / exposed	2 / 72 (2.78%)	1 / 74 (1.35%)	3 / 146 (2.05%)	1 / 37 (2.70%)
occurrences all number	2	1	3	1
Appendicitis
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	2	2	0
Biliary tract infection
subjects affected / exposed	2 / 72 (2.78%)	1 / 74 (1.35%)	3 / 146 (2.05%)	1 / 37 (2.70%)
occurrences all number	2	1	3	1
Bladder infection
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Bronchial infection
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Catheter related infection
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	1 / 37 (2.70%)
occurrences all number	0	1	1	1
Gallbladder infection
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	2	0	2	0
Hepatic infection
subjects affected / exposed	1 / 72 (1.39%)	1 / 74 (1.35%)	2 / 146 (1.37%)	1 / 37 (2.70%)
occurrences all number	2	2	4	1
Lung infection
subjects affected / exposed	6 / 72 (8.33%)	3 / 74 (4.05%)	9 / 146 (6.16%)	1 / 37 (2.70%)
occurrences all number	7	3	10	1
Infection without neutropenia NOS
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Paronychia
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Pleural infection
subjects affected / exposed	1 / 72 (1.39%)	0 / 74 (0.00%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	1	0	1	0
Sepsis
subjects affected / exposed	2 / 72 (2.78%)	2 / 74 (2.70%)	4 / 146 (2.74%)	1 / 37 (2.70%)
occurrences all number	2	2	4	1
Tooth infection
subjects affected / exposed	0 / 72 (0.00%)	1 / 74 (1.35%)	1 / 146 (0.68%)	0 / 37 (0.00%)
occurrences all number	0	1	1	0
Urinary tract infection
subjects affected / exposed	4 / 72 (5.56%)	0 / 74 (0.00%)	4 / 146 (2.74%)	0 / 37 (0.00%)
occurrences all number	4	0	4	0
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	7 / 72 (9.72%)	14 / 74 (18.92%)	21 / 146 (14.38%)	9 / 37 (24.32%)
occurrences all number	8	18	26	10
Dehydration
subjects affected / exposed	0 / 72 (0.00%)	2 / 74 (2.70%)	2 / 146 (1.37%)	1 / 37 (2.70%)
occurrences all number	0	2	2	1

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Were there any global substantial amendments to the protocol? Yes

19 May 2014

Amendment to the ICF due to changes to the safety language in the ICF.

26 Nov 2014

Amendment to add four additional participating institutions.

20 Jul 2015

Amendment of the protocol to adjust the timing of study procedures, to clarify inclusion/exclusion criteria and increase sample size from 110 to 143 due to observed patient compliance in providing QOL data.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
18 Jun 2015	Temporary interuption of recruitment at the completion of initial sample size on 18-Jun-2015. The protocol amendment to adjust the timing of study procedures, to clarify inclusion/exclusion criteria and increase sample size from 110 to 143 due to observed patient compliance in providing QOL data was approved on 17-Jul-2015 by the Belgian Health Authority (FAGG) and 20-Jul-2015 by the designated central ethics committee. Recruitment was restarted after all regulatory approvals on 24-Jul-2015.	24 Jul 2015

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

Quality of life endpoints are sensitive to confounding factors such as age, intercurrent disease, time from last completed questionnaire to the last follow-up or death. Tumour response and AE relationship to treatment were locally assessed.

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Clinical trials

Clinical Trial Results: Randomized crossover trial to assess the effects and quality of life in patients with locally advanced or metastatic pancreatic cancer treated with gemcitabine in combination with nab-paclitaxel: QOLINPAC

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Deterioration-free survival rate of the QOL global health status at 3, 6 and 12 months

Primary: Deterioration-free survival rate of the QOL global health status at 3, 6 and 12 months

Primary: QOL global health status deterioration-free median survival

Primary: QOL global health status deterioration-free median survival

Secondary: Deterioration-free survival rate of the QOL functional scales at 3, 6 and 12 months

Secondary: Deterioration-free survival rate of the QOL functional scales at 3, 6 and 12 months

Secondary: QOL functional scales deterioration-free median survival

Secondary: QOL functional scales deterioration-free median survival

Secondary: Deterioration-free survival rate of the QOL symptom scales at 3, 6 and 12 months

Secondary: Deterioration-free survival rate of the QOL symptom scales at 3, 6 and 12 months

Secondary: QOL symptom scales deterioration-free median survival

Secondary: QOL symptom scales deterioration-free median survival

Secondary: Exposure to treatment

Secondary: Exposure to treatment

Secondary: Overall response

Secondary: Overall response

Secondary: Duration of response (in responders)

Secondary: Duration of response (in responders)

Secondary: Disease control

Secondary: Disease control

Secondary: Progression rates at 1 year

Secondary: Progression rates at 1 year

Secondary: Progression free survival

Secondary: Progression free survival

Secondary: Death rates at 30 days from last treatment

Secondary: Death rates at 30 days from last treatment

Secondary: Death rates at 1 year

Secondary: Death rates at 1 year

Secondary: Overall survival

Secondary: Overall survival

Secondary: Laboratory safety assessment

Secondary: Laboratory safety assessment

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Randomized crossover trial to assess the effects and quality of life in patients with locally advanced or metastatic pancreatic cancer treated with gemcitabine in combination with nab-paclitaxel: QOLINPAC