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Clinical Trial Results:
A phase I/II study of nab-paclitaxel (Abraxane®) and gemcitabine followed by modified FOLFOX (AG-mFOLFOX) in patients with previously untreated, metastatic pancreatic adenocarcinoma

Summary
EudraCT number	2014-005350-19
Trial protocol	ES
Global end of trial date	10 Apr 2021

Results information
Results version number	v1(current)
This version publication date	22 Jun 2022
First version publication date	22 Jun 2022
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

TTD-14-05

ISRCTN number

US NCT number

NCT02504333

WHO universal trial number (UTN)

Sponsor organisation name

Spanish Cooperative for Digestive Tumour Therapy (TTD)

Sponsor organisation address

C/ Téllez no. 30 posterior, 1st floor, office 4-2/4-3, Madrid, Spain, 28007

Public contact

TTD, Spanish Cooperative for Digestive Tumour Therapy , 0034 91378 82 75, ttd@ttdgroup.org

Scientific contact

TTD, Spanish Cooperative for Digestive Tumour Therapy, 0034 91 378 82 75, ttd@ttdgroup.org

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

08 Apr 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Apr 2021

Was the trial ended prematurely?

Main objective of the trial

Phase I: - To determine the safety DLT for the AG-mFOLFOX combination. Phase II: Primary objective: - Clinical efficacy of AG-mFOLFOX vs AG as measured as % of overall survival al 12 months after treatment initiation. Secondary objective: - Overall survival rate at 6 months (% OS 6 months). - Overall survival rate at 24 months (% OS 24 months). - Time to progression (TTP). - Progression-free survival (PFS). - Overall survival (OS). - Objective radiographic response (ORR) according to RECIST. - CA 19.9 marker response. - Safety profile according to NCI-CTCAE version 4 criteria. - Quality of life of the patients based on the EORTC QLQ-C30/PAN26 and EORTC QLQ-CIPN20 questionnaires, which are specific for neurological toxicity.

Protection of trial subjects

This clinical study will be conducted in accordance with the protocol, the principles established in the latest version of the Declaration of Helsinki with regard to Good Clinical Practice, current regulations on clinical trials (Royal Decree 1090/2015 regulating clinical trials with medicinal products, the Ethics Committees for Research with medicinal products and the Spanish Clinical Studies Registry regulating clinical trials with medicinal products in Spain, and which incorporates in its entirety the regulations of European Directive 2001/20/EC regarding the provisions of the Member States on the implementation of Good Clinical Practice in the conduct of clinical trials with medicinal products for human use), as well as Act 14/2007, of 3 July on biomedical research, and Royal Decree 1716/2011, of 18 November, in all applicable aspects. The investigator agrees, on signing the protocol, to comply with the instructions and procedures described therein and, thus, to follow the principles of Good Clinical Practice they entail, as well as the applicable regulations. Furthermore, the investigator will ensure that the staff of his/her team is qualified by education, training, and experience to assume responsibility for the proper conduction of the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Oct 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

24 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 168

Worldwide total number of subjects

168

EEA total number of subjects

168

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

Patients were included in the phase I study from 08-10-2015 to 09-09-2016 in some centers in Spain. A total of 12 patients were recruited but 1 was screening failure. Patients were included in the phase II study from 27-7-2017 to 16-04-2019 in different centers in Spain. A total of 182 patients were recruited but 25 were screening failures.

Screening details

Patients recruited were ≥ 18 years, had metastatic pancreatic adenocarcinoma (stage IV), a 0-1 ECOG score, a measurable disease according to RECIST criteria version 1.1, an adequate liver, kidney and bone marrow function, and haven't been previously treated with systemic or investigational therapy for metastatic pancreatic cancer.

Period 1 title

Phase I/II trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase II, Arm A (Control): AG

Arm description

Nab-paclitaxel (Abraxane®) 125 mg/m2 administered intravenously over 30 minutes followed by gemcitabine 1000 mg/m2 administered intravenously over 30 minutes on days 1, 8, and 15 every 28 days (4 weeks).

Arm type

Active comparator

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

Other name

Abraxane®

Pharmaceutical forms

Powder for dispersion for injection

Routes of administration

Intravenous use

Dosage and administration details

Nab-paclitaxel (Abraxane®) 125 mg/m2 administered intravenously over 30 minutes on days 1, 8, and 15 every 28 days (4 weeks). This treatment will be repeated every 4 weeks (1 treatment cycle). The dose of the drugs will be calculated based on patient weight. The patient weight used in dose calculation will always be a whole number, so fractions of kg will not be considered in the final weight; for this purpose, body weight will always be rounded to the nearest kg unit.

Investigational medicinal product name

gemcitabine

Investigational medicinal product code

Other name

Gemzar®

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine 1000 mg/m2 administered intravenously over 30 minutes on days 1, 8, and 15 every 28 days (4 weeks). This treatment will be repeated every 4 weeks (1 treatment cycle). The dose of the drugs will be calculated based on patient weight. The patient weight used in dose calculation will always be a whole number, so fractions of kg will not be considered in the final weight; for this purpose, body weight will always be rounded to the nearest kg unit.

Phase II, Arm B: AG-mFOLFOX

Arm description

- AG: Nab-paclitaxel (Abraxane®) will be administered intravenously over 30 minutes, followed by gemcitabine intravenously over 30 minutes on days 1, 8 and 15 every 42 days (6 weeks), according to doses established in Phase I. - Modified FOLFOX-6 (mFOLFOX-6) administered on day 29 every 42 days (6 weeks), according to doses established in Phase I.

Arm type

Experimental

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

Other name

Abraxane®

Pharmaceutical forms

Powder for dispersion for injection

Routes of administration

Intravenous use

Dosage and administration details

Nab-paclitaxel (Abraxane®) was administered intravenously over 30 minutes on days 1, 8 and 15 every 42 days (6 weeks) according to doses established in Phase I detailed as follows: 125 mg/m2 i.v. 30’ administered on days 1, 8 and 15. The dose of the drugs was calculated based on patient weight. The patient weight used in dose calculation will always be a whole number, so fractions of kg were not considered in the final weight; for this purpose, body weight was always rounded to the nearest kg unit.

Investigational medicinal product name

gemcitabine

Investigational medicinal product code

Other name

Gemzar®

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine was administered intravenously over 30 minutes on days 1, 8 and 15 every 42 days (6 weeks) according to doses established in Phase I detailed as follows: 1000 mg/m2 i.v. 30’ administered on days 1, 8 and 15. The dose of the drugs was calculated based on patient weight. The patient weight used in dose calculation will always be a whole number, so fractions of kg were not considered in the final weight; for this purpose, body weight was always rounded to the nearest kg unit.

Investigational medicinal product name

mFOLFOX-6

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion, Injection/infusion, Powder for solution for infusion

Routes of administration

Intravenous bolus use , Intravenous use

Dosage and administration details

Modified FOLFOX-6 (mFOLFOX-6) administered on day 29 every 42 days (6 weeks), according to doses established in Phase I detailed below: Oxaliplatin: 85 mg/m2 i.v. 2 h, day 1, followed by or concomitant to (according to the practice at each site) leucovorin calcium (LV): 400 mg/m2 (racemic) or 200 mg/m2 (L-form) i.v., followed by fluorouracil (5-FU): 400 mg/m2 i.v. as bolus, followed by 5-FU: 2400 mg/m2 administered over 46 h as continuous infusion.

Phase I trial

Arm description

Six patients were enrolled at the highest dose level and then a 3 + 3 dose de-escalation schema was carried out. The criterion for de-escalation was more than one out of six patients reporting dose-limiting toxicity (DLT). A patient was evaluable at a given dose level, if had completed two cycles of treatment, comprising the two sequential schemes repeated twice, or have withdrawn from the study as result of a DLT. Each treatment cycle consisted of a 42-day period with therapy administered as follows: 30-min intravenous IV nab-paclitaxel infusion (125 mg/m2) followed by 30-min IV GEM infusion (1000 mg/m2) on days 1, 8 and 15 and 120-min IV oxaliplatin infusion (85 mg/m2), followed or concomitant (according to clinical practice) to 120-min IV L-leucovorin (200 mg/m2) or racemic leucovorin (400 mg/m2) infusion, followed by IV bolus of 5-FU (400 mg/m2) and followed by 46-h IV 5-FU infusion (2400 mg/m2) on day 29.

Arm type

dose de-escalation

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

Other name

Abraxane®

Pharmaceutical forms

Powder for dispersion for injection

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

gemcitabine

Investigational medicinal product code

Other name

Gemzar®

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

mFOLFOX-6

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion, Injection/infusion, Powder for solution for infusion

Routes of administration

Intravenous bolus use , Intravenous use

Dosage and administration details

Number of subjects in period 1	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX	Phase I trial
Started	79	78	11
Completed	4	12	5
Not completed	75	66	6
Consent withdrawn by subject	-	1	-
death of the patient	75	64	6
Lost to follow-up	-	1	-

Baseline characteristics

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Reporting group title

Phase II, Arm A (Control): AG

Reporting group description

Reporting group title

Phase II, Arm B: AG-mFOLFOX

Reporting group description

Reporting group title

Phase I trial

Reporting group description

Reporting group values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX	Phase I trial	Total
Number of subjects	79	78	11	168
Age categorical
Units: Subjects
≤65 años	44	38	8	90
>65 años	35	40	3	78
Age continuous
Units: years
arithmetic mean (standard deviation)	64.0 ± 10.0	64.6 ± 8.9	60.1 ± 9.0	-
Gender categorical
Units: Subjects
Female	43	37	5	85
Male	36	41	6	83
ECOG scale
The ECOG Performance Status Scale describes a patient’s level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.). ECOG performance grade: • ECOG 0: The patient is completely asymptomatic and is able to perform normal work and activities of daily living. • ECOG 1: The patient has symptoms that prevent him/her from doing hard work, although he/she performs normally in daily activities and light work. The patient only stays in bed during night sleep.
Units: Subjects
ECOG 0	22	22	4	48
ECOG 1	57	56	7	120
Baseline medical history
Does the patient present relevant past or active pathological history and/or symptoms related to the disease under study?
Units: Subjects
No	4	5	2	11
Yes	75	73	9	157
TNM grade at diagnosis
Stage 0: Cancer in situ. Stage IA: Tumor is ≤ 2 cm in the pancreas. It has not spread to lymph nodes or other parts. Stage IB: Tumor is > 2 cm in the pancreas. It has not spread to lymph nodes or other parts. Stage IIA: Tumor is > 4 cm and extends beyond the pancreas. It has not spread to lymph nodes, or other parts. Stage IIB: Tumor of any size. It has spread to 1 to 3 regional lymph nodes but not to other parts Stage III: Tumor of any size. It has spread ≥ 4 regional lymph nodes but not to other parts, or has spread to nearby arteries and veins Stage IV: Tumor has spread along the body
Units: Subjects
IA	1	0	0	1
IB	1	0	0	1
IIA	2	0	0	2
IIB	1	3	1	5
III	4	3	0	7
IV	70	71	10	151
Unknown	0	1	0	1
Pancreatic tumour location: Head
Units: Subjects
No	47	48	6	101
Yes	32	30	5	67
Pancreatic tumour location: body
Units: Subjects
No	51	47	6	104
Yes	28	31	5	64
Pancreatic tumour location: tail
Units: Subjects
No	51	51	7	109
Yes	28	27	4	59
Pancreatic tumour location: Uncinate process
Units: Subjects
No	79	74	10	163
Yes	0	4	1	5
Pancreatic tumour location: unknown
Units: Subjects
No	79	76	10	165
Yes	0	2	1	3
Metastasis
Units: Subjects
Synchronous	75	74	9	158
Metachronous	4	4	2	10
Current location of tumors: liver
Units: Subjects
No	20	18	0	38
Yes	59	60	11	130
Current location of tumors: lungs
Units: Subjects
No	59	51	10	120
Yes	20	27	1	48
Current location of tumors: peritoneum
Units: Subjects
No	54	57	10	121
Yes	25	21	1	47
Current location of tumors: pancreas
Units: Subjects
No	8	11	1	20
Yes	71	67	10	148
Current location of tumors: regional lymph nodes
Units: Subjects
No	64	62	10	136
Yes	15	16	1	32
Current location of tumors: distant lymph nodes
Units: Subjects
No	66	63	11	140
Yes	13	15	0	28
Current location of tumors: stomach
Units: Subjects
No	79	77	11	167
Yes	0	1	0	1
Current location of tumors: large intestine
Units: Subjects
No	78	77	11	166
Yes	1	1	0	2
Current location of tumors: bones
Units: Subjects
No	78	73	10	161
Yes	1	5	1	7
Current location of tumors: other parts of the body
Units: Subjects
No	70	62	9	141
Yes	9	16	2	27
Number of organs involved
Units: Subjects
1 organ	3	2	1	6
2 organs	35	26	7	68
3 organs	27	31	2	60
4 organs	10	12	1	23
5 organs	4	5	0	9
6 organs	0	2	0	2
Patients with at least one previous surgery
Units: Subjects
No surgery	66	63	10	139
Surgery	13	15	1	29
Previous chemotherapy for pancreatic cancer
Units: Subjects
No	77	73	11	161
Yes	2	5	0	7
Previous radiotherapy
The intention of radiotherapy has been adjuvant.
Units: Subjects
No	78	78	11	167
Yes	1	0	0	1
Weight
Units: Kg
arithmetic mean (standard deviation)	68.7 ± 15.4	67.5 ± 13.2	71.4 ± 14.4	-
Height
Units: cm
arithmetic mean (standard deviation)	163.3 ± 8.4	164.1 ± 8.8	165.9 ± 10.7	-
Body surface
Units: m2
arithmetic mean (standard deviation)	1.7 ± 0.2	1.7 ± 0.2	1.8 ± 0.2	-
Time since initial diagnosis of pancreatic cancer
Time from initial diagnosis of pancreatic cancer to inclusion in the study (Inclusion date - Diagnosis date).
Units: months
arithmetic mean (standard deviation)	2.0 ± 4.7	2.6 ± 6.0	1.1 ± 0.9	-
Time since diagnosis of metastatic pancreatic cancer
Time from diagnosis of metastatic pancreatic cancer to inclusion in the study (Date of inclusion - Date of diagnosis of metastatic cancer).
Units: months
arithmetic mean (standard deviation)	0.9 ± 0.7	1.3 ± 3.1	1.0 ± 0.9	-

End points

Top of page

Reporting group title

Phase II, Arm A (Control): AG

Reporting group description

Reporting group title

Phase II, Arm B: AG-mFOLFOX

Reporting group description

Reporting group title

Phase I trial

Reporting group description

Primary: Maximum-tolerated dose (MTD) evaluation

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End point title

Maximum-tolerated dose (MTD) evaluation ^[1] ^[2]

End point description

Six patients were enrolled at the highest dose level and then a 3 + 3 dose de-escalation schema was carried out. The criterion for de-escalation was more than one out of six patients reporting dose-limiting toxicity (DLT). A patient was evaluable at a given dose level, if had completed two cycles of treatment, or have withdrawn from the study as result of a DLT. Treatment continued until disease progression, unacceptable toxicity or consent withdrawal. New treatment cycle was not started until absolute neutrophil count ≥1500/mL, platelet count ≥100 000/mL, serum bilirubin level ≤1.5 x upper limit of normal, creatinine clearance level ≥40 mL/min and recovery from other clinically significant non-haematologic toxicities (except alopecia) <Grade 2. If the patient did not meet these criteria, treatment was delayed until these requirements were met. Patients who required a treatment delay of >4 weeks were removed. Note: there was no reduction in the dose of folinic acid.

End point type

Primary

End point timeframe

Two cycles of treatment of 42 days

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: This is a single-arm phase I clinical trial, therefore, no statistical analysis was performed for this endpoint.
[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: The maximum-tolerated dose was only evaluated for patients in the Phase I part of the trial as defined in the study protocol.

End point values	Phase I trial
Number of subjects analysed	6 ^[3]
Units: mg/m2
number (not applicable)
Nab-paclitaxel	125
Gemcitabine	1000
mFOLFOX: Oxaliplatin	85
mFOLFOX: 5-FU bolus	400
mFOLFOX: 5-FU infusion	2400

Notes
[3] - Five patients were excluded for not completing two cycles of treatment.

No statistical analyses for this end point

Primary: Overall survival rate at 12 months

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End point title

Overall survival rate at 12 months ^[4]

End point description

Overall survival rate at 12 months is defined as the percentage of patients alive 12 months after inclusion in the study. To calculate this, an analysis will be made using the Kaplan-Meier method. The Kaplan-Meier plot, median survival and 95% confidence interval was calculated, and the number of events and censored events as well. The 12-month live patient rate and its 95% confidence interval is provided below.

End point type

Primary

End point timeframe

12 months

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: The overall survival rate at 12 months was only evaluated for patients in the Phase II part of the trial as defined in the study protocol.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: Percentage (%)
number (confidence interval 95%)	35.4 (24.9 to 46.0)	55.3 (44.2 to 66.5)

Fisher's exact test

Statistical analysis description

Fisher's exact test is a statistical significance test used in the analysis of contingency tables to analyze whether two dichotomous variables are associated when the sample to be studied is too small.

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.016 ^[5]

Method

Fisher exact

Confidence interval

Notes
[5] - Overall survival rate of AG-mFOLFOX-6 is significantly higher than AG (Control).

Secondary: Preliminary efficacy assessment

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End point title

Preliminary efficacy assessment ^[6]

End point description

The preliminary efficacy was assessed by the Objective Response Rate (ORR) and the Disease Control Rate (DCR). ORR is the percentage of patients with advanced or metastatic cancer in a clinical study who have a partial or complete response to the treatment according to RECIST 1.1 criteria within a certain period of time. A partial response (PR) is a decrease in the size of a tumor or in the amount of cancer in the body, and a complete response (CR) is the disappearance of all signs of cancer in the body. DCR is defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease (SD) to a therapeutic intervention in clinical trials of anticancer agents.

End point type

Secondary

End point timeframe

October 2015- September 2016.

Notes
[6] - 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: The preliminary efficacy assessment was only evaluated for patients in the Phase I part of the trial as defined in the study protocol.

End point values	Phase I trial
Number of subjects analysed	10 ^[7]
Units: Percentage (%)
number (confidence interval 95%)
Objective response rate (CR=0; PR=5)	50 (20.1 to 79.9)
Disease control rate (CR=0; PR=5; SD=3)	80 (44.2 to 96.5)

Notes
[7] - One patient died before the first CT.

No statistical analyses for this end point

Secondary: Overall survival rate at 6 months

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End point title

Overall survival rate at 6 months ^[8]

End point description

Overall survival rate at 6 months is defined as the percentage of patients alive 6 months after inclusion in the study. To calculate this, an analysis will be made using the Kaplan-Meier method. The Kaplan-Meier plot, median survival and 95% confidence interval was calculated, and the number of events and censored events as well. The 6-month live patient rate and its 95% confidence interval is provided below.

End point type

Secondary

End point timeframe

6 months

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: The overall survival rate at 6 months was only evaluated for patients in the Phase II part of the trial as defined in the study protocol.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: Percentage (%)
number (confidence interval 95%)	69.6 (59.5 to 79.8)	73.8 (63.9 to 83.7)

Fisher's exact test

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.598 ^[9]

Method

Fisher exact

Confidence interval

Notes
[9] - No statistically significant

Secondary: Overall survival rate at 24 months

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End point title

Overall survival rate at 24 months ^[10]

End point description

Overall survival rate at 24 months is defined as the percentage of patients alive 24 months after inclusion in the study. To calculate this, an analysis will be made using the Kaplan-Meier method. The Kaplan-Meier plot, median survival and 95% confidence interval was calculated, and the number of events and censored events as well. The 24-month live patient rate and its 95% confidence interval is provided below.

End point type

Secondary

End point timeframe

24 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: The overall survival rate at 24 months was only evaluated for patients in the Phase II part of the trial as defined in the study protocol.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: Percentage (%)
number (confidence interval 95%)	7.6 (1.8 to 13.4)	22.4 (13.0 to 31.8)

Fisher's exact test

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.012

Method

Fisher exact

Confidence interval

Secondary: Time to progression (TTP)

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End point title

Time to progression (TTP) ^[11]

End point description

TTP is the length of time from the date of diagnosis or the start of treatment for a disease until the disease starts to get worse or spread to other parts of the body. The analysis was made using the Kaplan-Meier method estimating median time to progression and 95% confidence interval. Patients who have not shown disease progression or death were censored at the date of the last response assessment. If a patient has several response evaluations showing disease progression, the first of these evaluations was used in the time to progression analysis. Patients who are given a new treatment (radiotherapy or chemotherapy, other treatments) and have not progressed or have documented progression or death following the initiation of that new treatment have been censored at the date of initiation of that treatment, even if this is the treatment under study. Patients in whom no tumor assessments are available after the baseline assessment have been censored on day 1.

End point type

Secondary

End point timeframe

From the date of randomization/inclusion of treatment until the patient progresses or dies due to disease progression.

Notes
[11] - 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: Time to progression was only evaluated for patients in the Phase II part of the trial as defined in the study protocol.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: month
median (confidence interval 95%)	5.296 (3.285 to 7.307)	9.276 (5.840 to 12.713)

Log rank test

Statistical analysis description

The log rank test is a statistical methodology for comparing the distribution of time until the occurrence of an event of interest in independent groups.

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[12]

Method

Logrank

Parameter type

Odds ratio (OR)

Confidence interval

Notes
[12] - Time to progression for AG-mFOLFOX regimen is statistically higher than for AG regimen.

Cox regression

Statistical analysis description

The Cox proportional-hazards model is essentially a regression model commonly used statistical in medical research for investigating the association between the survival time of patients and one or more predictor variables.

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[13]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.462

Confidence interval

level

95%

sides

2-sided

lower limit

0.319

upper limit

0.669

Notes
[13] - Time to progression for AG-mFOLFOX regimen is statistically higher than for AG regimen.

Secondary: Progression-free survival (PFS)

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End point title

Progression-free survival (PFS) ^[14]

End point description

PFS is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse. The analysis was made using the Kaplan-Meier method estimating median progression-free survival and 95% confidence interval. Patients who have not shown disease progression or death were censored at the date of the last response assessment. If a patient has several response evaluations showing disease progression, the first of these evaluations was used in the time to progression analysis. Patients who are given a new treatment (radiotherapy or chemotherapy, other treatments) and have not progressed or have documented progression or death following the initiation of that new treatment have been censored at the date of initiation of that treatment, even if this is the treatment under study. Patients in whom no tumor assessments are available after the baseline assessment have been censored on day 1.

End point type

Secondary

End point timeframe

From the date of randomization/inclusion of treatment until the patient progresses or dies of any cause.

Notes
[14] - 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: Progression-free survival was only evaluated for patients in the Phase II part of the trial as defined in the study protocol.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: months
median (confidence interval 95%)	5.164 (3.278 to 7.051)	7.895 (6.207 to 9.583)

Log rank test

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[15]

Method

Logrank

Parameter type

Odds ratio (OR)

Confidence interval

Notes
[15] - Free-progression survival for AG-mFOLFOX regimen is statistically higher than for AG regimen.

Cox regression

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[16]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.516

Confidence interval

level

95%

sides

2-sided

lower limit

0.363

upper limit

0.734

Notes
[16] - Free-progression survival for AG-mFOLFOX regimen is statistically higher than for AG regimen.

Secondary: Overall survival (OS)

Top of page

End point title

Overall survival (OS) ^[17]

End point description

Overall survival is the time elapsed from the date of randomization/inclusion until the patient dies of any cause. In the rest of the patients, the last available follow-up was taken as the last control. The analysis was made using the Kaplan-Meier method estimating median overall survival and 95% confidence interval.

End point type

Secondary

End point timeframe

From the date of randomization/inclusion until the patient dies of any cause.

Notes
[17] - 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: The overall survival was only evaluated for patients in the Phase II part of the trial as defined in the study protocol.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: months
median (confidence interval 95%)	9.737 (7.477 to 11.997)	13.158 (10.072 to 16.243)

Log rank test

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.022 ^[18]

Method

Logrank

Parameter type

Odds ratio (OR)

Confidence interval

Notes
[18] - Overall survival for AG-mFOLFOX regimen is statistically higher than for AG regimen.

Cox regression

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.023 ^[19]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.676

Confidence interval

level

95%

sides

2-sided

lower limit

0.483

upper limit

0.947

Notes
[19] - Overall survival for AG-mFOLFOX regimen is statistically higher than for AG regimen.

Secondary: Best overall response

Top of page

End point title

Best overall response ^[20]

End point description

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence according to RECIST criteria: - Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. - Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. - Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. - Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. - NE: not evaluated.

End point type

Secondary

End point timeframe

36 months

Notes
[20] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: patients
Complete response (CR)	0	4
Partial response (PR)	22	36
Stable disease (SD)	32	22
Progressive disease (PD)	17	7
NE	8	9

Fisher's exact test

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008

Method

Fisher exact

Confidence interval

Secondary: Objective response rate (ORR)

Top of page

End point title

Objective response rate (ORR) ^[21]

End point description

ORR is the percentage of patients with advanced or metastatic cancer in a clinical study who have a partial or complete response to the treatment according to RECIST 1.1 criteria within a certain period of time. A partial response (PR) is a decrease in the size of a tumor or in the amount of cancer in the body, and a complete response (CR) is the disappearance of all signs of cancer in the body.

End point type

Secondary

End point timeframe

36 months

Notes
[21] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: percentage (%)
number (confidence interval 95%)	27.8 (18.4 to 39.1)	51.3 (39.7 to 62.8)

Fisher's exact test

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[22]

Method

Fisher exact

Confidence interval

Notes
[22] - ORR of AG-mFOLFOX regimen is significantly higher than ORR of AG regimen (control).

Secondary: Confirmed best overall response

Top of page

End point title

Confirmed best overall response ^[23]

End point description

The best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation according to RECIST criteria.

End point type

Secondary

End point timeframe

36 months

Notes
[23] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: patients
Complete response (CR)	0	3
Partial response (PR)	16	28
Stable disease (SD)	38	31
Progressive response (PR)	17	7
Not evaluated (NE)	8	9

Fisher's exact test

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.022

Method

Fisher exact

Confidence interval

Secondary: Confirmed ORR

Top of page

End point title

Confirmed ORR ^[24]

End point description

End point type

Secondary

End point timeframe

36 months

Notes
[24] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: percentage (%)
median (confidence interval 95%)	20.3 (12.4 to 30.8)	39.7 (28.8 to 51.5)

Fisher's exact test

Comparison groups

Phase II, Arm B: AG-mFOLFOX v Phase II, Arm A (Control): AG

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.009 ^[25]

Method

Fisher exact

Confidence interval

Notes
[25] - Confirmed ORR of AG-mFOLFOX regimen is significantly higher than ORR of AG regimen (control).

Secondary: CA 19-9 levels

Top of page

End point title

CA 19-9 levels ^[26]

End point description

This test measures the amount of a protein called CA 19-9 (cancer antigen 19-9) in the blood. CA 19-9 is a type of tumor marker. CA 19-9 was analyzed at baseline visit (within 14 days prior to study inclusion/randomization) and at each evaluation visit (every 8 ± 2 weeks regardless of delays and/or cycles administered).

End point type

Secondary

End point timeframe

36 months

Notes
[26] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79 ^[27]	78 ^[28]
Units: U/mL
median (inter-quartile range (Q1-Q3))
Baseline visit (NA=75; NB= 73)	398.2 (28.4 to 2918.0)	861.0 (92.2 to 10634.1)
Evaluation visit 1 (NA=68; NB=64)	170.5 (16.3 to 982.3)	228.7 (21.1 to 3841.3)
Evaluation visit 2 (NA=49; NB=55)	117.3 (19.3 to 564.3)	83.4 (13.6 to 1308.0)
Evaluation visit 3 (NA=32; NB=47)	48.1 (6.4 to 772.0)	50.0 (8.8 to 558.5)
Evaluation visit 4 (NA=23; NB=37)	117.8 (12.0 to 1315.0)	39.6 (8.0 to 385.1)
Evaluation visit 5 (NA=15; NB=35)	30.9 (5.2 to 1586.5)	25.3 (8.9 to 450.3)
Evaluation visit 6 (NA=9; NB=24)	21.2 (8.2 to 168.6)	21.1 (7.5 to 61.4)
Evaluation visit 7 (NA=8; NB=23)	42.9 (8.1 to 101.6)	47.4 (9.0 to 215.0)
Evaluation visit 8 (NA=4; NB=18)	47.8 (8.2 to 705.0)	19.3 (8.4 to 122.8)
Evaluation visit 9 (NA=1; NB=17)	11.3 (11.3 to 11.3)	66.0 (16.0 to 714.7)
Evaluation visit 10 (NA=1; NB=11)	19.1 (19.1 to 19.1)	49.4 (15.0 to 249.9)
Evaluation visit 11 (NA=1; NB=9)	14.9 (14.9 to 14.9)	30.3 (14.6 to 429.7)
Evaluation visit 12 (NA=1; NB=8)	14.9 (14.9 to 14.9)	174.7 (14.3 to 1081.6)
Evaluation visit 13 (NA=0; NB=4)	0 (0 to 0)	246.3 (14.0 to 1667.5)
Evaluation visit 14 (NA=0; NB=4)	0 (0 to 0)	16.2 (12.6 to 934.7)
Evaluation visit 15 (NA=0; NB=3)	0 (0 to 0)	19.9 (13.8 to 1221.4)
Evaluation visit 16 (NA=0; NB=3)	0 (0 to 0)	22.9 (18.5 to 1257.2)

Notes
[27] - NA indicates the number of patients analyzed in arm A at each visit
[28] - NB indicates the number of patients analyzed in arm B at each visit.

Evaluation 3 (aprox. 6 months)

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.795

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Evaluation 6 (aprox. 12 months)

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.919

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Evaluation 12 (aprox. 24 months)

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.439

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: EORTC QLQ-C30 scale (cycle 1)

Top of page

End point title

EORTC QLQ-C30 scale (cycle 1) ^[29]

End point description

Quality of life questionnaire specific for neurological toxicity. The scores for each dimension have been calculated according to the scoring algorithms (QLQ C30 SCmanual/ ISBN 2-9300 64-22-6 /Third edition, 2001).

End point type

Secondary

End point timeframe

First cycle (day 1)

Notes
[29] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79 ^[30]	78 ^[31]
Units: score
arithmetic mean (standard deviation)
Global health status/Qol (NA=67; NB=61)	47.5 ± 22.5	54.4 ± 25.7
Physical functioning (NA=67; NB=60)	74.0 ± 24.0	80.4 ± 19.0
Role functioning (NA=67; NB=61)	60.7 ± 33.9	73.2 ± 30.0
Emotional functioning (NA=66; NB=61)	67.2 ± 20.9	68.3 ± 22.2
Cognitive functioning (NA=67; NB=61)	85.3 ± 22.2	88.0 ± 19.5
Social functioning (NA=64; NB=60)	69.5 ± 28.1	74.2 ± 26.6
Fatigue (NA=67; NB=61)	40.9 ± 28.0	34.8 ± 29.4
Nausea and vomiting (NA=67; NB=61)	9.7 ± 17.4	11.2 ± 22.3
Pain (NA=67; NB=61)	44.8 ± 30.3	35.0 ± 29.5
Dyspnoea (NA=65; NB=60)	13.8 ± 25.6	13.9 ± 28.3
Insomnia (NA=67; NB=60)	67.2 ± 28.7	66.1 ± 31.6
Appetite loss (NA=67; NB=61)	44.8 ± 37.9	31.7 ± 34.1
Constipation (NA=66; NB=61)	36.9 ± 36.1	31.1 ± 35.4
Diarrhoea (NA=67; NB=61)	10.9 ± 23.5	12.6 ± 23.7
Financial difficulties (NA=65; NB=61)	15.9 ± 26.4	20.8 ± 27.3

Notes
[30] - NA indicates number of patients analyzed in arm A for every item at cycle 1
[31] - NB indicates the number of patients analyzed in arm B for every item at cycle 1

Role functioning

Statistical analysis description

There are no statistical differences in the other items.

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.028

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: EORTC QLQ-C30 scale (cycle 2)

Top of page

End point title

EORTC QLQ-C30 scale (cycle 2) ^[32]

End point description

End point type

Secondary

End point timeframe

Second cycle (day 1)

Notes
[32] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79 ^[33]	78 ^[34]
Units: score
arithmetic mean (standard deviation)
Global health status/Qol (NA=60; NB=53)	54.6 ± 17.9	62.1 ± 20.3
Physical functioning (NA=61; NB=53)	70.7 ± 24.8	80.5 ± 17.6
Role functioning (NA=61; NB=53)	60.9 ± 34.8	71.1 ± 28.3
Emotional functioning (NA=59; NB=52)	65.8 ± 25.7	78.2 ± 17.9
Cognitive functioning (NA=59; NB= 53)	85.9 ± 19.8	92.1 ± 12.1
Social functioning (NA= 59; NB=53)	65.5 ± 27.1	68.6 ± 24.6
Fatigue (NA=61; NB=53)	43.9 ± 29.4	37.7 ± 24.3
Nausea and vomiting (NA=61; NB=53)	10.4 ± 16.4	10.1 ± 20.0
Pain (NA=61; NB=53)	27.3 ± 25.3	22.3 ± 23.8
Dyspnoea (NA=59; NB=53)	10.7 ± 19.0	10.7 ± 25.5
Insomnia (NA=61; NB=53)	57.9 ± 27.1	54.7 ± 22.7
Appetite loss (NA=60; NB=53)	31.7 ± 32.7	22.6 ± 29.8
Constipation (NA=61; NB=53)	18.6 ± 30.1	26.4 ± 31.6
Diarrhoea (NA=59; NB=52)	22.6 ± 31.2	21.8 ± 32.9
Financial difficulties (NA=59; NB=53)	17.5 ± 27.2	25.2 ± 30.6

Notes
[33] - NA indicates the number of patients analyzed in arm A for every item at cycle 2
[34] - NB indicates the number of patients analyzed in arm B for every item at cycle 2

Global health status/Qol

Statistical analysis description

We only display analysis of those items with statistical differences

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Physical functioning

Statistical analysis description

We only display analysis of those items with statistical differences

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.048

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Emotional functioning

Statistical analysis description

We only display analysis of those items with statistical differences

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.011

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: EORTC QLQ-C30 scale (end of treatment)

Top of page

End point title

EORTC QLQ-C30 scale (end of treatment) ^[35]

End point description

End point type

Secondary

End point timeframe

visit at end of treatment

Notes
[35] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79 ^[36]	78 ^[37]
Units: score
arithmetic mean (standard deviation)
Global health status/Qol (NA=39; NB=29)	51.7 ± 22.5	52.0 ± 26.2
Physical functioning (NA=39; NB=30)	65.1 ± 29.8	70.4 ± 24.2
Role functioning (NA=39; NB=30)	58.1 ± 35.6	61.1 ± 32.9
Emotional functioning (NA=39; NB=29)	63.9 ± 30.2	65.8 ± 24.7
Cognitive functioning (NA=39; NB= 29)	79.5 ± 25.8	81.0 ± 23.9
Social functioning (NA= 39; NB=29)	59.0 ± 34.8	63.8 ± 31.5
Fatigue (NA=39; NB=30)	47.9 ± 29.6	42.2 ± 32.0
Nausea and vomiting (NA=39; NB=29)	8.5 ± 17.5	10.9 ± 16.8
Pain (NA=39; NB=29)	32.5 ± 33.5	29.9 ± 27.2
Dyspnoea (NA=39; NB=30)	19.7 ± 28.3	16.7 ± 28.7
Insomnia (NA=39; NB=29)	53.0 ± 28.3	54.0 ± 28.7
Appetite loss (NA=39; NB=29)	30.8 ± 32.8	26.4 ± 32.6
Constipation (NA=39; NB=30)	21.4 ± 31.1	22.2 ± 28.1
Diarrhoea (NA=39; NB=29)	11.1 ± 23.4	12.6 ± 20.7
Financial difficulties (NA=39; NB=29)	24.8 ± 34.8	25.3 ± 27.7

Notes
[36] - NA indicates the number of patients analyzed in arm A for every item at end of treatment.
[37] - NB indicates the number of patients analyzed in arm B for every item at end of treatment

EORTC QLQ-C30 at end of treatment

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

> 0.05 ^[38]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[38] - No significantly differences among items of this questionnaire at end of treatment

Secondary: EORTC QLQ-PAN26 scale (Cycle 1)

Top of page

End point title

EORTC QLQ-PAN26 scale (Cycle 1) ^[39]

End point description

The QLQ-PAN26 consists of seven hypothesized scales to assess pancreatic pain, digestive symptoms, altered bowel habit, hepatic, body image, satisfaction with health care, and sexuality. In addition, ten single items measure other issues related to pancreatic cancer. Users should be aware though that the scaling structure is still preliminary. All of the scales and single item measures range in score from 0 to 100.

End point type

Secondary

End point timeframe

First cycle (day 1)

Notes
[39] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79 ^[40]	78 ^[41]
Units: score
arithmetic mean (standard deviation)
Pancreatic pain (NA=66; NB=61)	38.6 ± 28.6	33.2 ± 25.8
Bloating (NA=66; NB=61)	32.3 ± 33.6	31.1 ± 34.4
Digestive symptoms (NA=65; NB=61)	41.0 ± 32.6	28.7 ± 29.0
Taste (NA=66; NB=60)	23.7 ± 31.9	19.4 ± 29.0
Indigestion (NA=65; NB=60)	19.0 ± 26.3	9.4 ± 17.5
Flatulence (NA=66; NB=61)	42.9 ± 34.0	44.3 ± 33.2
Weight loss (NA=64; NB=61)	42.2 ± 37.2	37.7 ± 33.0
Weakness arms and legs (NA=66; NB=61)	35.9 ± 34.2	29.0 ± 28.9
Dry mouth (NA=66; NB=61)	44.9 ± 37.2	30.6 ± 35.1
Hepatic symptoms (NA=65; NB=61)	13.1 ± 21.1	10.9 ± 16.9
Troubled with side-effects (NA=59; NB=45)	22.0 ± 31.3	18.5 ± 28.9
Future Worries (NA=65; NB=61)	70.8 ± 31.5	66.1 ± 31.3
Planning of activities (NA=63; NB=58)	29.6 ± 34.4	36.2 ± 33.8
Satisfaction with health care (NA=65; NB=61)	56.2 ± 23.7	61.5 ± 22.7
Sexuality (NA=57; NB=52)	45.6 ± 40.9	44.6 ± 37.9
Altered bowel habit (NA=65; NB=60)	19.2 ± 26.2	15.8 ± 22.4
Body image (NA=65; NB=61)	26.9 ± 34.6	15.3 ± 19.3

Notes
[40] - NA indicates the number of patients of arm A analyzed for every item at day 1 of cycle 1.
[41] - NB indicates the number of patients of arm B analyzed for every item at day 1 of cycle 1.

Digestive symptoms

Statistical analysis description

We only display analysis of those items with statistical differences

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.033

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Indigestion

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.033

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Dry mouth

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.026

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: EORTC QLQ-PAN26 scale (Cycle 4)

Top of page

End point title

EORTC QLQ-PAN26 scale (Cycle 4) ^[42]

End point description

End point type

Secondary

End point timeframe

Day 1 of cycle 4

Notes
[42] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79 ^[43]	78 ^[44]
Units: score
arithmetic mean (standard deviation)
Pancreatic pain (NA=37; NB=44)	14.3 ± 18.2	11.9 ± 13.6
Bloating (NA=36; NB=44)	19.4 ± 24.4	16.7 ± 21.0
Digestive symptoms (NA=37; NB=44)	22.5 ± 24.9	18.6 ± 23.1
Taste (NA=36; NB=44)	46.3 ± 35.9	34.8 ± 27.8
Indigestion (NA=35; NB=44)	8.6 ± 21.9	6.8 ± 15.4
Flatulence (NA=37; NB=43)	40.5 ± 29.5	41.9 ± 32.6
Weight loss (NA=36; NB=44)	41.7 ± 35.1	27.3 ± 29.9
Weakness arms and legs (NA=37; NB=44)	36.9 ± 35.8	25.8 ± 24.8
Dry mouth (NA=36; NB=44)	43.5 ± 37.2	24.2 ± 25.3
Hepatic symptoms (NA=37; NB=44)	11.7 ± 16.1	6.1 ± 14.4
Altered bowel habit (NA=37; NB=44)	22.1 ± 29.4	17.0 ± 22.9
Body image (NA=34; NB=44)	31.9 ± 32.1	23.5 ± 23.4
Troubled with side-effects (NA=33; NB=44)	43.4 ± 30.6	31.1 ± 23.2
Future Worries (NA=35; NB=43)	61.9 ± 33.5	45.7 ± 29.1
Planning of activities (NA=35; NB=43)	30.5 ± 32.7	48.8 ± 32.0
Satisfaction with health care (NA=35; NB=44)	54.3 ± 21.1	68.9 ± 17.8
Sexuality (NA=27; NB=34)	25.9 ± 34.7	48.0 ± 37.8

Notes
[43] - NA indicates the number of patients of arm A analyzed for every item at day 1 of cycle 4.
[44] - NB indicates the number of patients of arm B analyzed for every item at day 1 of cycle 4.

Dry mouth

Statistical analysis description

We only display those items with statistical differences.

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.021

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Hepatic symptoms

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.034

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Future worries

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.023

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Planning of activities

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.015

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Satisfaction with health care

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Sexuality

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.02

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: EORTC QLQ-PAN26 scale (end of treatment)

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End point title

EORTC QLQ-PAN26 scale (end of treatment) ^[45]

End point description

End point type

Secondary

End point timeframe

End of treatment

Notes
[45] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: score
arithmetic mean (standard deviation)
Pancreatic pain (NA=39; NB=29)	27.1 ± 27.4	27.3 ± 25.2
Bloating (NA=39; NB=29)	25.6 ± 34.6	26.4 ± 34.9
Digestive symptoms (NA=39; NB=30)	29.5 ± 30.2	25.0 ± 24.7
Taste (NA=39; NB=30)	35.9 ± 33.7	34.4 ± 30.9
Indigestion (NA=39; NB=29)	15.4 ± 26.3	16.1 ± 26.2
Flatulence (NA=38; NB=30)	41.2 ± 34.2	43.3 ± 29.2
Weight loss (NA=39; NB=29)	37.6 ± 36.8	28.7 ± 35.3
Weakness arms and legs (NA=39; NB=30)	41.9 ± 31.3	35.6 ± 33.8
Dry mouth (NA=37; NB=30)	41.4 ± 38.0	37.8 ± 33.6
Hepatic symptoms (NA=39; NB=30)	9.4 ± 17.4	15.6 ± 27.7
Altered bowel habit (NA=39; NB=30)	14.1 ± 22.1	25.6 ± 25.8
Body image (NA=38; NB=29)	38.6 ± 35.3	28.7 ± 31.1
Troubled with side-effects (NA=37; NB=29)	47.7 ± 31.0	46.0 ± 33.8
Future Worries (NA=38; NB=29)	62.3 ± 33.0	63.2 ± 33.7
Planning of activities (NA=36; NB=28)	36.1 ± 35.1	27.4 ± 28.8
Satisfaction with health care (NA=37; NB=29)	58.6 ± 21.7	55.2 ± 20.9
Sexuality (NA=28; NB=23)	32.7 ± 40.2	47.8 ± 39.7

Altered bowel habit

Statistical analysis description

We only show those items with statistically differences

Comparison groups

Phase II, Arm B: AG-mFOLFOX v Phase II, Arm A (Control): AG

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.029

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: EORTC QLQ-CIPN20 scale (Cycle 1)

Top of page

End point title

EORTC QLQ-CIPN20 scale (Cycle 1) ^[46]

End point description

The CIPN20 module includes 20 items, conceptualised as consisting of 3 scales: 1. Sensory scale: Items 1-6, 9, 10 and 18 address sensory symptoms and problems. It is hypothesized that these items will form a multi-item scale. The individual items and the multi-item scale should be scored such that higher scores represent more symptoms/problems (i.e., higher score = worse). 2. Motor scale: Items 7, 8, 11-15 and 19 address motor symptoms and problems. It is hypothesized that these items, excluding item 19, will form a multi-item scale. Item 19 is conditional on driving a car, and thus is not relevant to all patients. Thus, it should be treated as a separate item. 3. Autonomic scale: Items 16, 17 and 20 assess autonomic symptoms and problems. Items 16 and 17 are hypothesized to form a two-item scale. Item 20 is relevant only for men, and thus should be treated as a separate item.

End point type

Secondary

End point timeframe

First cycle (day 1)

Notes
[46] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79 ^[47]	78 ^[48]
Units: score
arithmetic mean (standard deviation)
Sensory Scale (NA=63; NB=57)	92.6 ± 11.8	96.3 ± 5.1
Motor scale (NA=63; NB=57)	89.9 ± 14.8	95.5 ± 5.6
Item 19 (NA=27; NB=32)	96.3 ± 14.1	99.0 ± 5.9
Automatic scale (NA=63; NB=57)	90.2 ± 16.6	93.0 ± 14.1
Item 20 (NA=22; NB=25)	54.5 ± 41.8	57.3 ± 42.5

Notes
[47] - NA indicates number of patients analyzed in arm A for every item at cycle 1
[48] - NB indicates number of patients analyzed in arm B for every item at cycle 1

Motor scale

Statistical analysis description

There are no statistical differences in the other items.

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.026

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: EORTC QLQ-CIPN20 scale (Cycle 2)

Top of page

End point title

EORTC QLQ-CIPN20 scale (Cycle 2) ^[49]

End point description

End point type

Secondary

End point timeframe

Second cycle (day 1)

Notes
[49] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79 ^[50]	78 ^[51]
Units: Score
arithmetic mean (standard deviation)
Sensory Scale (NA=57; NB=49)	94.1 ± 7.3	86.1 ± 11.4
Motor scale (NA=57; NB=49)	92.8 ± 8.5	87.7 ± 11.3
Item 19 (NA=23; NB=24)	100.0 ± 0.0	93.1 ± 24.0
Automatic scale (NA=57; NB=49)	85.7 ± 18.8	85.0 ± 19.6
Item 20 (NA=23; NB=18)	55.1 ± 41.0	61.1 ± 41.6

Notes
[50] - NA indicates number of patients analyzed in arm A for every item at cycle 2
[51] - NB indicates number of patients analyzed in arm B for every item at cycle 2

Sensory scale

Statistical analysis description

We only display analysis of those items with statistical differences

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Motor scale

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.015

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Secondary: EORTC QLQ-CIPN20 scale (end of treatment)

Top of page

End point title

EORTC QLQ-CIPN20 scale (end of treatment) ^[52]

End point description

End point type

Secondary

End point timeframe

End of treatment

Notes
[52] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79 ^[53]	78 ^[54]
Units: Score
arithmetic mean (standard deviation)
Sensory Scale (NA=38; NB=29)	76.8 ± 24.5	82.2 ± 18.1
Motor scale (NA=38; NB=29)	78.7 ± 22.8	84.7 ± 18.6
Item 19 (NA=13; NB=16)	82.1 ± 32.2	97.9 ± 8.3
Automatic scale (NA=37; NB=29)	80.6 ± 20.6	82.8 ± 21.1
Item 20 (NA=14; NB=13)	33.3 ± 41.3	46.2 ± 42.0

Notes
[53] - NA indicates number of patients analyzed in arm A for every item at end of treatment
[54] - NB indicates number of patients analyzed in arm B for every item at end of treatment

EORTC QLQ-CIPN20 scale at end of treatment

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

> 0.05 ^[55]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[55] - There are no statistical differences for any item.

Secondary: Disease Control Rate (DCR)

Top of page

End point title

Disease Control Rate (DCR) ^[56]

End point description

DCR is defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials according to Recist 1.1

End point type

Secondary

End point timeframe

36 months

Notes
[56] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: percentage (%)
number (confidence interval 95%)	68.4 (56.9 to 78.4)	79.5 (68.8 to 87.8)

Fisher's exact test

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.146

Method

Fisher exact

Confidence interval

Secondary: Confirmed DCR

Top of page

End point title

Confirmed DCR ^[57]

End point description

End point type

Secondary

End point timeframe

36 months

Notes
[57] - 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 Phase II subjects were analyzed in this endpoint.

End point values	Phase II, Arm A (Control): AG	Phase II, Arm B: AG-mFOLFOX
Number of subjects analysed	79	78
Units: Percentage (%)
number (confidence interval 95%)	68.4 (56.9 to 78.4)	79.5 (68.8 to 87.8)

Fisher's exact test

Comparison groups

Phase II, Arm A (Control): AG v Phase II, Arm B: AG-mFOLFOX

Number of subjects included in analysis

157

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.146

Method

Fisher exact

Confidence interval

Adverse events

Top of page

Timeframe for reporting adverse events

From 8/10/15 to 10/04/21.

Adverse event reporting additional description

The investigator must record all AEs occurring from the time the patient signs the informed consent until 28 days after the last dose of the investigational medicinal product. Adverse events, especially those whose relationship with the investigational drug is “suspicious”, will be monitored until they have resolved or returned to baseline values.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Phase I safety population

Reporting group description

It's defined as all patients who have received at least one administration of the study drugs

Reporting group title

Phase II arm A safety population

Reporting group description

The safety analysis includes all patients who have received at least one administration of the study drugs.

Reporting group title

Phase II arm B safety population

Reporting group description

The safety analysis includes all patients who have received at least one administration of the study drugs.

Serious adverse events	Phase I safety population	Phase II arm A safety population	Phase II arm B safety population
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 11 (45.45%)	47 / 79 (59.49%)	41 / 76 (53.95%)
number of deaths (all causes)	6	75	62
number of deaths resulting from adverse events	2	12	7
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 11 (9.09%)	2 / 79 (2.53%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Condition aggravated
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
General physical health deterioration
subjects affected / exposed	0 / 11 (0.00%)	3 / 79 (3.80%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 1
Pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 11 (0.00%)	2 / 79 (2.53%)	3 / 76 (3.95%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic shock
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	3 / 76 (3.95%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Completed suicide
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Confusional state
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Blood bilirubin increased
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Gastrointestinal toxicity
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 11 (9.09%)	0 / 79 (0.00%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ischaemic cerebral infarction
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Radiculopathy
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 11 (0.00%)	2 / 79 (2.53%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 11 (0.00%)	2 / 79 (2.53%)	5 / 76 (6.58%)
occurrences causally related to treatment / all	0 / 0	2 / 2	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Splenic infarction
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	2 / 76 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2
Diarrhoea
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	7 / 76 (9.21%)
occurrences causally related to treatment / all	0 / 0	1 / 1	7 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 11 (9.09%)	2 / 79 (2.53%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 1	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Gastrointestinal toxicity
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Intestinal obstruction
subjects affected / exposed	0 / 11 (0.00%)	4 / 79 (5.06%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Intra-abdominal fluid collection
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 11 (9.09%)	0 / 79 (0.00%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	0 / 11 (0.00%)	2 / 79 (2.53%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholangitis acute
subjects affected / exposed	1 / 11 (9.09%)	0 / 79 (0.00%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 11 (0.00%)	2 / 79 (2.53%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Jaundice cholestatic
subjects affected / exposed	0 / 11 (0.00%)	2 / 79 (2.53%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Infections and infestations
Abdominal infection
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Biliary tract infection
subjects affected / exposed	1 / 11 (9.09%)	0 / 79 (0.00%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 11 (0.00%)	3 / 79 (3.80%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
COVID-19
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 11 (0.00%)	6 / 79 (7.59%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 11 (0.00%)	5 / 79 (6.33%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	1 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 11 (0.00%)	3 / 79 (3.80%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	1 / 1
Septic shock
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 11 (0.00%)	4 / 79 (5.06%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypocalcaemia
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Phase I safety population	Phase II arm A safety population	Phase II arm B safety population
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 11 (100.00%)	79 / 79 (100.00%)	76 / 76 (100.00%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 11 (0.00%)	13 / 79 (16.46%)	6 / 76 (7.89%)
occurrences all number	0	21	7
Aspartate aminotransferase increased
subjects affected / exposed	0 / 11 (0.00%)	6 / 79 (7.59%)	5 / 76 (6.58%)
occurrences all number	0	8	5
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 11 (0.00%)	6 / 79 (7.59%)	1 / 76 (1.32%)
occurrences all number	0	8	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 11 (0.00%)	7 / 79 (8.86%)	5 / 76 (6.58%)
occurrences all number	0	8	7
Transaminases increased
subjects affected / exposed	0 / 11 (0.00%)	3 / 79 (3.80%)	9 / 76 (11.84%)
occurrences all number	0	3	12
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 11 (9.09%)	6 / 79 (7.59%)	1 / 76 (1.32%)
occurrences all number	1	7	1
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 11 (0.00%)	3 / 79 (3.80%)	4 / 76 (5.26%)
occurrences all number	0	3	4
Dysaesthesia
subjects affected / exposed	3 / 11 (27.27%)	2 / 79 (2.53%)	9 / 76 (11.84%)
occurrences all number	4	2	20
Dysgeusia
subjects affected / exposed	0 / 11 (0.00%)	12 / 79 (15.19%)	12 / 76 (15.79%)
occurrences all number	0	14	15
Paraesthesia
subjects affected / exposed	5 / 11 (45.45%)	5 / 79 (6.33%)	18 / 76 (23.68%)
occurrences all number	12	5	27
Peripheral sensory neuropathy
subjects affected / exposed	2 / 11 (18.18%)	30 / 79 (37.97%)	43 / 76 (56.58%)
occurrences all number	3	91	173
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	6 / 11 (54.55%)	37 / 79 (46.84%)	42 / 76 (55.26%)
occurrences all number	22	63	108
Febrile neutropenia
subjects affected / exposed	0 / 11 (0.00%)	4 / 79 (5.06%)	6 / 76 (7.89%)
occurrences all number	0	4	6
Leukopenia
subjects affected / exposed	3 / 11 (27.27%)	4 / 79 (5.06%)	18 / 76 (23.68%)
occurrences all number	9	5	39
Neutropenia
subjects affected / exposed	8 / 11 (72.73%)	33 / 79 (41.77%)	50 / 76 (65.79%)
occurrences all number	30	77	248
Thrombocytopenia
subjects affected / exposed	6 / 11 (54.55%)	27 / 79 (34.18%)	50 / 76 (65.79%)
occurrences all number	18	85	239
General disorders and administration site conditions
Asthenia
subjects affected / exposed	9 / 11 (81.82%)	53 / 79 (67.09%)	62 / 76 (81.58%)
occurrences all number	14	154	233
Fatigue
subjects affected / exposed	0 / 11 (0.00%)	5 / 79 (6.33%)	2 / 76 (2.63%)
occurrences all number	0	6	2
General physical health deterioration
subjects affected / exposed	0 / 11 (0.00%)	4 / 79 (5.06%)	2 / 76 (2.63%)
occurrences all number	0	5	2
Mucosal inflammation
subjects affected / exposed	2 / 11 (18.18%)	10 / 79 (12.66%)	15 / 76 (19.74%)
occurrences all number	3	15	26
Oedema
subjects affected / exposed	0 / 11 (0.00%)	5 / 79 (6.33%)	1 / 76 (1.32%)
occurrences all number	0	5	1
Oedema peripheral
subjects affected / exposed	0 / 11 (0.00%)	20 / 79 (25.32%)	11 / 76 (14.47%)
occurrences all number	0	28	17
Pain
subjects affected / exposed	0 / 11 (0.00%)	5 / 79 (6.33%)	3 / 76 (3.95%)
occurrences all number	0	5	3
Pyrexia
subjects affected / exposed	6 / 11 (54.55%)	22 / 79 (27.85%)	24 / 76 (31.58%)
occurrences all number	8	55	52
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 11 (9.09%)	2 / 79 (2.53%)	4 / 76 (5.26%)
occurrences all number	1	4	6
Abdominal pain
subjects affected / exposed	1 / 11 (9.09%)	21 / 79 (26.58%)	16 / 76 (21.05%)
occurrences all number	1	30	23
Abdominal pain upper
subjects affected / exposed	1 / 11 (9.09%)	5 / 79 (6.33%)	9 / 76 (11.84%)
occurrences all number	1	5	9
Constipation
subjects affected / exposed	3 / 11 (27.27%)	20 / 79 (25.32%)	18 / 76 (23.68%)
occurrences all number	3	25	30
Diarrhoea
subjects affected / exposed	4 / 11 (36.36%)	33 / 79 (41.77%)	42 / 76 (55.26%)
occurrences all number	5	72	98
Nausea
subjects affected / exposed	4 / 11 (36.36%)	29 / 79 (36.71%)	35 / 76 (46.05%)
occurrences all number	5	44	74
Stomatitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 79 (1.27%)	10 / 76 (13.16%)
occurrences all number	0	3	23
Vomiting
subjects affected / exposed	2 / 11 (18.18%)	24 / 79 (30.38%)	23 / 76 (30.26%)
occurrences all number	2	31	30
Respiratory, thoracic and mediastinal disorders
Catarrh
subjects affected / exposed	0 / 11 (0.00%)	3 / 79 (3.80%)	6 / 76 (7.89%)
occurrences all number	0	4	12
Cough
subjects affected / exposed	0 / 11 (0.00%)	4 / 79 (5.06%)	3 / 76 (3.95%)
occurrences all number	0	4	4
Dyspnoea
subjects affected / exposed	0 / 11 (0.00%)	4 / 79 (5.06%)	4 / 76 (5.26%)
occurrences all number	0	5	7
Epistaxis
subjects affected / exposed	0 / 11 (0.00%)	4 / 79 (5.06%)	8 / 76 (10.53%)
occurrences all number	0	5	11
Pneumothorax
subjects affected / exposed	0 / 11 (0.00%)	0 / 79 (0.00%)	4 / 76 (5.26%)
occurrences all number	0	0	5
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	2 / 11 (18.18%)	21 / 79 (26.58%)	23 / 76 (30.26%)
occurrences all number	3	21	31
Erythema
subjects affected / exposed	0 / 11 (0.00%)	5 / 79 (6.33%)	6 / 76 (7.89%)
occurrences all number	0	6	6
Pruritus
subjects affected / exposed	0 / 11 (0.00%)	5 / 79 (6.33%)	5 / 76 (6.58%)
occurrences all number	0	7	5
Rash
subjects affected / exposed	0 / 11 (0.00%)	7 / 79 (8.86%)	9 / 76 (11.84%)
occurrences all number	0	8	10
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 11 (0.00%)	5 / 79 (6.33%)	9 / 76 (11.84%)
occurrences all number	0	5	13
Back pain
subjects affected / exposed	1 / 11 (9.09%)	5 / 79 (6.33%)	10 / 76 (13.16%)
occurrences all number	1	5	11
Musculoskeletal pain
subjects affected / exposed	2 / 11 (18.18%)	1 / 79 (1.27%)	8 / 76 (10.53%)
occurrences all number	5	1	8
Myalgia
subjects affected / exposed	1 / 11 (9.09%)	3 / 79 (3.80%)	5 / 76 (6.58%)
occurrences all number	1	3	8
Pain in extremity
subjects affected / exposed	0 / 11 (0.00%)	6 / 79 (7.59%)	3 / 76 (3.95%)
occurrences all number	0	6	3
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 11 (0.00%)	6 / 79 (7.59%)	4 / 76 (5.26%)
occurrences all number	0	9	4
Pneumonia
subjects affected / exposed	0 / 11 (0.00%)	6 / 79 (7.59%)	1 / 76 (1.32%)
occurrences all number	0	6	1
Respiratory tract infection
subjects affected / exposed	0 / 11 (0.00%)	10 / 79 (12.66%)	8 / 76 (10.53%)
occurrences all number	0	13	9
Urinary tract infection
subjects affected / exposed	0 / 11 (0.00%)	10 / 79 (12.66%)	5 / 76 (6.58%)
occurrences all number	0	13	5
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 11 (18.18%)	30 / 79 (37.97%)	29 / 76 (38.16%)
occurrences all number	2	48	48

More information

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Were there any global substantial amendments to the protocol? Yes

04 Jan 2016

Version 2 of 4 January 2016

17 Mar 2017

Addition of sites. Amendments not applicable to the protocol, and therefore no new version is generated.

11 Jul 2017

Update of sites. Amendments not applicable to the protocol, and therefore no new version is generated.

16 Feb 2018

Change of investigator. Amendments not applicable to the protocol, and therefore no new version is generated.

21 Jan 2019

Amendments not applicable to the protocol, and therefore no new version is generated.

04 Dec 2019

Version 3 of 4 December 2019

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

http://www.ncbi.nlm.nih.gov/pubmed/32977220

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Clinical trials

Clinical Trial Results: A phase I/II study of nab-paclitaxel (Abraxane®) and gemcitabine followed by modified FOLFOX (AG-mFOLFOX) in patients with previously untreated, metastatic pancreatic adenocarcinoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximum-tolerated dose (MTD) evaluation

Primary: Maximum-tolerated dose (MTD) evaluation

Primary: Overall survival rate at 12 months

Primary: Overall survival rate at 12 months

Secondary: Preliminary efficacy assessment

Secondary: Preliminary efficacy assessment

Secondary: Overall survival rate at 6 months

Secondary: Overall survival rate at 6 months

Secondary: Overall survival rate at 24 months

Secondary: Overall survival rate at 24 months

Secondary: Time to progression (TTP)

Secondary: Time to progression (TTP)

Secondary: Progression-free survival (PFS)

Secondary: Progression-free survival (PFS)

Secondary: Overall survival (OS)

Secondary: Overall survival (OS)

Secondary: Best overall response

Secondary: Best overall response

Secondary: Objective response rate (ORR)

Secondary: Objective response rate (ORR)

Secondary: Confirmed best overall response

Secondary: Confirmed best overall response

Secondary: Confirmed ORR

Secondary: Confirmed ORR

Secondary: CA 19-9 levels

Secondary: CA 19-9 levels

Secondary: EORTC QLQ-C30 scale (cycle 1)

Secondary: EORTC QLQ-C30 scale (cycle 1)

Secondary: EORTC QLQ-C30 scale (cycle 2)

Secondary: EORTC QLQ-C30 scale (cycle 2)

Secondary: EORTC QLQ-C30 scale (end of treatment)

Secondary: EORTC QLQ-C30 scale (end of treatment)

Secondary: EORTC QLQ-PAN26 scale (Cycle 1)

Secondary: EORTC QLQ-PAN26 scale (Cycle 1)

Secondary: EORTC QLQ-PAN26 scale (Cycle 4)

Secondary: EORTC QLQ-PAN26 scale (Cycle 4)

Secondary: EORTC QLQ-PAN26 scale (end of treatment)

Secondary: EORTC QLQ-PAN26 scale (end of treatment)

Secondary: EORTC QLQ-CIPN20 scale (Cycle 1)

Secondary: EORTC QLQ-CIPN20 scale (Cycle 1)

Secondary: EORTC QLQ-CIPN20 scale (Cycle 2)

Secondary: EORTC QLQ-CIPN20 scale (Cycle 2)

Secondary: EORTC QLQ-CIPN20 scale (end of treatment)

Secondary: EORTC QLQ-CIPN20 scale (end of treatment)

Secondary: Disease Control Rate (DCR)

Secondary: Disease Control Rate (DCR)

Secondary: Confirmed DCR

Secondary: Confirmed DCR

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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Clinical Trial Results:
A phase I/II study of nab-paclitaxel (Abraxane®) and gemcitabine followed by modified FOLFOX (AG-mFOLFOX) in patients with previously untreated, metastatic pancreatic adenocarcinoma