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Clinical Trial Results:
Phase 1/2 Study of anti-PD-L1 in Combination with Chemo(radio)therapy for Oesophageal Cancer

Summary
EudraCT number	2015-005298-19
Trial protocol	GB
Global end of trial date	17 Jun 2022

Results information
Results version number	v1(current)
This version publication date	15 Dec 2022
First version publication date	15 Dec 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

LUD2015-005

ISRCTN number

US NCT number

NCT02735239

WHO universal trial number (UTN)

Sponsor organisation name

Ludwig Institute for Cancer Research Ltd

Sponsor organisation address

600 3rd Avenue 32nd Floor, New York, United States, 10016

Public contact

Jonathan Skipper, Ludwig Institute for Cancer Research Ltd, 001 2124501539, jskipper@lcr.org

Scientific contact

Jonathan Skipper , Ludwig Institute for Cancer Research Ltd, 001 2124501539, jskipper@lcr.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

28 Jul 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

17 Jun 2022

Global end of trial reached?

Yes

Global end of trial date

17 Jun 2022

Was the trial ended prematurely?

Main objective of the trial

The main objectives are (1) to assess the safety and tolerability of durvalumab alone and tremelimumab + durvalumab in combination with oxaliplatin/capecitabine chemotherapy in metastatic or locally advanced oesophageal cancer (OC), and then (2) to assess the safety and tolerability of durvalumab in combination with neoadjuvant chemo(radio)therapy before surgery in operable oesophageal cancer. Secondary objectives are (1) to assess the clinical efficacy of durvalumab alone and tremelimumab + durvalumab in combination with oxaliplatin/capecitabine chemotherapy in metastatic or locally advanced OC. (Endpoints: Tumor Response by irRECIST, progression-free survival [PFS] and overall survival [OS]) and (2) to assess the clinical efficacy of durvalumab in combination with neoadjuvant chemo(radio)therapy (oxaliplatin/capecitabine, FLOT, and paclitaxel/carboplatin/radiotherapy) in operable OC. (Endpoints: PFS after surgery, 1-year survival rate, OS, response rate)

Protection of trial subjects

Subjects were given full and adequate written information about the nature, purpose and possible risks and benefits of the study. Dose adjustments, delays and discontinuation criteria were included in the protocol in the form of dose adjustment and management guidelines for toxicity related to study treatment. Phase 1 of the study (Cohorts A1 and A2) evaluated the feasibility/safety of administering durvalumab or tremelimumab + durvalumab pre-operatively to OC subjects. Once safety was established in these cohorts, the additional cohorts were open for enrollment. In addition, safety monitoring and study stopping rules were implemented in the protocol. The assessment of safety and tolerability was performed by the internal data safety monitoring panel on an ongoing basis, based on data review and regular conference calls with the investigators. Standard safety evaluation and reporting for early phase trials were used for Cohorts B, C/C-FLOT, and D/D2. In addition, for Cohorts C/C-FLOT and D/D2, subjects undergoing surgery were closely monitored for post-operative complications to evaluate the possibility of an impact. Laboratory tests, vital sign measurements, physical exams (including neurological exams) and subject interviews were performed to detect new abnormalities and deteriorations of any pre-existing conditions. The investigator evaluated any laboratory abnormalities for clinical significance, and clinically significant abnormalities were recorded as adverse events. All clinically significant abnormalities and deteriorations from time of signing of informed consent to the end of study visit were to be recorded in the Case Report Forms as adverse events and graded according to the National Cancer Institute Common Terminology for Adverse Events (CTCAE), version 4.03.

Background therapy

The fluoropyrimidine–platinum (traditionally 5FU-cisplatin) based CRT regimen has long been a standard of care in the pre-operative management of oesophageal cancer. The use of this combination was largely historic, with only one small positive trial, and several meta-analyses supporting its use over surgery alone. The oxaliplatin-capecitabine based CRT regimen was selected over the cisplatin-fluoropyrimidine regime for Cohorts A, B & C based on several factors including maintaining the same chemotherapy backbone in the metastatic or locally advanced OC Cohorts A & B as in the Cohort C neoadjuvant chemotherapy arm of the trial. This decision was based on a randomized Phase 2 study in definitive chemoradiation showing comparable efficacy and less toxicity of oxaliplatin-5FU combination in comparison to cisplatin-5FU combination, emerging Phase 1b/2 data suggesting feasibility and activity of oxaliplatin-fluoropyrimidine based CRT regimens in the pre-operative setting and use of this regimen in the NEOSCOPE trial, a randomized Phase 2 trial that was ongoing in the UK at the time when this protocol was being developed. While the trial was ongoing, two additional background treatments were added for subjects with operable OC based on emerging data. In Cohort C-FLOT, oxaliplatin and capecitabine as neoadjuvant chemotherapy was replaced with the FLOT regimen to run concurrently with durvalumab treatment, and introducing post-operative chemotherapy, also with FLOT. This was to run concurrently with durvalumab immunotherapy. In Cohort D, 2 doses of durvalumab were to be given during a 4-week immunotherapy period, followed by neoadjuvant chemoradiotherapy (5 weekly doses of paclitaxel + carboplatin + radiotherapy) without concurrent durvalumab. Cohort D2 is a subset of Cohort D subjects for whom durvalumab doses were to continue during chemoradiotherapy, after the initial 4-week immunotherapy.

Evidence for comparator

Actual start date of recruitment

22 Apr 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 73

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment was from 22 April 2016 to 31 December 2019. Seventy-nine subjects were assessed for eligibility, 6 were excluded and 73 were recruited for treatment. The study included 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion Phase 2, Cohorts B, C, C-FLOT and D/D2.

Screening details

Screening was completed within 28 days of the start of therapy. Subjects must have had a histological diagnosis of oesophageal or gastroesophageal cancer and have not received prior chemotherapy. Cohorts A and B - metastatic/locally advanced cancer. Cohorts C, C-FLOT and D/D2 - deemed suitable for surgery with curative intent.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort A1

Arm description

Metastatic/locally Advanced Oesophageal Cancer, Durvalumab + Oxaliplatin/Capecitabine Chemotherapy

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

MEDI4736

Other name

Imfinzi

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Durvalumab (750 mg every two weeks [Q2W]) was to be given for up to 11 doses.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Eloxatin

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin (130 mg/m^2) was administered by intravenous infusion in six three-week cycles starting on the day of the third dose of durvalumab.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Xeloda

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine (1250 mg/m^2/day) was given orally in two divided doses for six three-week cycles starting on the day of the first oxaliplatin infusion.

Cohort A2

Arm description

Metastatic/locally Advanced Oesophageal Cancer, Durvalumab, Tremelimumab + Oxaliplatin/Capecitabine Chemotherapy

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

MEDI4736

Other name

Imfinzi

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Durvalumab (750 mg every two weeks [Q2W]) was to be given for up to 11 doses.

Investigational medicinal product name

Tremelimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

One dose of tremelimumab (37.5 mg) was given by intravenous infusion on the same day as the first dose of durvalumab.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Eloxatin

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin (130 mg/m^2) was administered by intravenous infusion in six three-week cycles starting on the day of the third dose of durvalumab.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Xeloda

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine (1250 mg/m^2/day) was given orally in two divided doses for six three-week cycles starting on the day of the first oxaliplatin infusion.

Cohort B

Arm description

Metastatic/locally Advanced Oesophageal Cancer, Durvalumab, Tremelimumab + Oxaliplatin/Capecitabine Chemotherapy

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

MEDI4736

Other name

Imfinzi

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Durvalumab (750 mg every two weeks [Q2W]) was to be given for up to 11 doses.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Xeloda

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine (1250 mg/m^2/day) was given orally in two divided doses for six three-week cycles starting on the day of the first oxaliplatin infusion.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Eloxatin

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin (130 mg/m^2) was administered by intravenous infusion in six three-week cycles starting on the day of the third dose of durvalumab.

Investigational medicinal product name

Tremelimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

One dose of tremelimumab (75 mg) was given by intravenous infusion on the same day as the first dose of durvalumab.

Cohort C

Arm description

Operable Oesophageal Cancer, Durvalumab + Oxaliplatin/Capecitabine Chemotherapy

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

MEDI4736

Other name

Imfinzi

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Durvalumab (750 mg every two weeks [Q2W]) was given for 11 doses.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Eloxatin

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin (130 mg/m^2) was administered by intravenous infusion in six three-week cycles starting on the day of the third dose of durvalumab.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Xeloda

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine (1250 mg/m^2/day) was given orally in two divided doses for six three-week cycles starting on the day of the first oxaliplatin infusion.

Cohort C-FLOT

Arm description

Operable Oesophageal Cancer, Durvalumab + Neoadjuvant 5-fluorouracil (5-FU), Leucovorin, Oxaliplatin, and Docetaxel (FLOT) Chemotherapy

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

MEDI4736

Other name

Imfinzi

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Durvalumab (750 mg every two weeks [Q2W]) was to be given for 6 doses prior to surgery. Optional durvalumab for up to a total of 12 doses was allowed after recovery from surgery provided this was within 3 months of surgery.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Eloxatin

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

As part of two cycles of neoadjuvant FLOT chemotherapy, oxaliplatin (85 mg/m^2) was administered by intravenous infusion before surgery starting on the day of the third dose of durvalumab. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions), FLOT or durvalumab plus FLOT at the discretion of the Investigator once recovered from surgery, provided that this was within 3 months of surgery.

Investigational medicinal product name

5-Flourouracil

Investigational medicinal product code

Other name

5-FU

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

As part of two cycles of neoadjuvant FLOT chemotherapy, 5-fluorouracil (5-FU) (2600 mg/m^2) was administered as a 24-hr infusion before surgery starting on the day of the third dose of durvalumab. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions), FLOT or durvalumab plus FLOT at the discretion of the Investigator once recovered from surgery, provided that this was within 3 months of surgery.

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

As part of two cycles of neoadjuvant FLOT chemotherapy, leucovorin (200 mg/m^2 IV), was administered before surgery starting on the day of the third dose of durvalumab. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions), FLOT or durvalumab plus FLOT at the discretion of the Investigator once recovered from surgery, provided that this was within 3 months of surgery.

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Taxotere

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

As part of two cycles of neoadjuvant FLOT chemotherapy, docetaxel (50 mg/m^2) was administered before surgery starting on the day of the third dose of durvalumab. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions), FLOT or durvalumab plus FLOT at the discretion of the Investigator once recovered from surgery, provided that this was within 3 months of surgery.

Cohort D/D2

Arm description

Operable Oesophageal Cancer, Durvalumab + Neoadjuvant Chemo(radio)therapy with Paclitaxel, Carboplatin and Radiotherapy.

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

MEDI4736

Other name

Imfinzi

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Durvalumab (750 mg every two weeks [Q2W]) was to be given for 2 doses (Cohort D) or 5 doses (Cohort D2) prior to surgery. Optional durvalumab dosing was allowed after recovery from surgery for up to 12 total doses provided that this was within 3 months of surgery.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Taxol

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Five weekly doses of paclitaxel (50 mg/m^2) by intravenous infusion as part of neoadjuvant chemoradiotherapy (41.4 Gy radiotherapy given over 23 fractions) were administered before surgery. In Cohort D2, subjects continued durvalumab for 3 additional doses while receiving chemoradiation. Subjects were to undergo surgery 6 to 8 weeks after completing chemo(radio)therapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Paraplatin

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Five weekly doses of carboplatin (AUC 2) by intravenous infusion as part of neoadjuvant chemoradiotherapy (41.4 Gy radiotherapy given over 23 fractions) were administered before surgery. In Cohort D2, subjects continued durvalumab for 3 additional doses while receiving chemoradiation. Subjects were to undergo surgery 6 to 8 weeks after completing chemo(radio)therapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.

Number of subjects in period 1	Cohort A1	Cohort A2	Cohort B	Cohort C	Cohort C-FLOT	Cohort D/D2
Started	12	5	21	11	9	15
Completed	8	2	13	11	9	13
Not completed	4	3	8	0	0	2
Adverse event, serious fatal	1	1	-	-	-	-
Consent withdrawn by subject	-	1	-	-	-	-
Physician decision	-	-	1	-	-	-
Adverse event, non-fatal	-	-	4	-	-	-
Progressive disease	3	1	3	-	-	2

Baseline characteristics

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Reporting group title

Cohort A1

Reporting group description

Metastatic/locally Advanced Oesophageal Cancer, Durvalumab + Oxaliplatin/Capecitabine Chemotherapy

Reporting group title

Cohort A2

Reporting group description

Metastatic/locally Advanced Oesophageal Cancer, Durvalumab, Tremelimumab + Oxaliplatin/Capecitabine Chemotherapy

Reporting group title

Cohort B

Reporting group description

Metastatic/locally Advanced Oesophageal Cancer, Durvalumab, Tremelimumab + Oxaliplatin/Capecitabine Chemotherapy

Reporting group title

Cohort C

Reporting group description

Operable Oesophageal Cancer, Durvalumab + Oxaliplatin/Capecitabine Chemotherapy

Reporting group title

Cohort C-FLOT

Reporting group description

Operable Oesophageal Cancer, Durvalumab + Neoadjuvant 5-fluorouracil (5-FU), Leucovorin, Oxaliplatin, and Docetaxel (FLOT) Chemotherapy

Reporting group title

Cohort D/D2

Reporting group description

Operable Oesophageal Cancer, Durvalumab + Neoadjuvant Chemo(radio)therapy with Paclitaxel, Carboplatin and Radiotherapy.

Reporting group values	Cohort A1	Cohort A2	Cohort B	Cohort C	Cohort C-FLOT	Cohort D/D2	Total
Number of subjects	12	5	21	11	9	15	73
Age categorical
Units: Subjects
Adults (18-64 years)	7	3	16	8	6	7	47
From 65-84 years	5	2	5	3	3	8	26
Age continuous
Units: years
median (full range (min-max))	59.5 (23 to 75)	55.0 (29 to 67)	58.0 (42 to 78)	57.0 (46 to 71)	56.0 (33 to 72)	65.0 (50 to 72)	-
Gender categorical
Units: Subjects
Female	2	1	4	0	1	3	11
Male	10	4	17	11	8	12	62

End points

Top of page

Reporting group title

Cohort A1

Reporting group description

Metastatic/locally Advanced Oesophageal Cancer, Durvalumab + Oxaliplatin/Capecitabine Chemotherapy

Reporting group title

Cohort A2

Reporting group description

Metastatic/locally Advanced Oesophageal Cancer, Durvalumab, Tremelimumab + Oxaliplatin/Capecitabine Chemotherapy

Reporting group title

Cohort B

Reporting group description

Metastatic/locally Advanced Oesophageal Cancer, Durvalumab, Tremelimumab + Oxaliplatin/Capecitabine Chemotherapy

Reporting group title

Cohort C

Reporting group description

Operable Oesophageal Cancer, Durvalumab + Oxaliplatin/Capecitabine Chemotherapy

Reporting group title

Cohort C-FLOT

Reporting group description

Operable Oesophageal Cancer, Durvalumab + Neoadjuvant 5-fluorouracil (5-FU), Leucovorin, Oxaliplatin, and Docetaxel (FLOT) Chemotherapy

Reporting group title

Cohort D/D2

Reporting group description

Operable Oesophageal Cancer, Durvalumab + Neoadjuvant Chemo(radio)therapy with Paclitaxel, Carboplatin and Radiotherapy.

Primary: Number of Subjects With Best Overall Tumor Response by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)

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End point title

Number of Subjects With Best Overall Tumor Response by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) ^[1]

End point description

Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), and in Cycles 1, 3, 5 and 6 in Cohorts A1, A2 and B. In the other cohorts, tumor response was assessed at baseline, post-surgery and 14 days after the last dose. In Cohort C-FLOT, an additional assessment was done prior to surgery and in Cohorts C and D, an additional assessment was done in Cycle 3. Per irRECIST, measurable lesions are categorized as follows: Immune-related Complete Response (irCR): Complete disappearance of all target lesions; Immune-related Partial Response (irPR): ≥ 30% decrease from baseline in the total measurable tumor burden (TMTB); Immune-related Progressive Disease (irPD): ≥ 20% increase from nadir in TMTB; Immune-related Stable Disease (irSD): not meeting above criteria; irNon-CR/Non-PD: not evaluable.

End point type

Primary

End point timeframe

up to 1 year

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: In this study where different regimens are being studied in each Cohort, the primary objective was to assess the safety of the different regimens and sample sizes were determined based on this. While secondary objectives were to obtain preliminary efficacy of each regimen, the intent was not to compare the regimens and as a results no statistical comparisons were made between cohorts.

End point values	Cohort A1	Cohort A2	Cohort B	Cohort C	Cohort C-FLOT	Cohort D/D2
Number of subjects analysed	11	5	20	9	5	8
Units: subjects
irCR	2	0	0	3	1	2
irPR	3	3	10	1	0	0
irSD	5	1	4	0	0	0
irPD	1	1	5	1	0	1
irNon-CR/Non-PD	0	0	1	1	0	0
Not Evaluable	0	0	0	3	4	5

No statistical analyses for this end point

Secondary: Number of Subjects With Metastatic/locally Advanced Oesophageal Cancer (OC) Who Had a Response at Cycle 6 by irRECIST

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End point title

Number of Subjects With Metastatic/locally Advanced Oesophageal Cancer (OC) Who Had a Response at Cycle 6 by irRECIST ^[2]

End point description

Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), and in Cycles 1, 3, 5 and 6 in Cohorts A1, A2 and B. Per irRECIST, measurable lesions are categorized as follows: irCR: Complete disappearance of all target lesions; irPR: ≥ 30% decrease from baseline in the total measurable tumor burden (TMTB); irPD: ≥ 20% increase from nadir in TMTB; irSD: not meeting above criteria; irNon-CR/Non-PD: not evaluable.

End point type

Secondary

End point timeframe

Up to 23 weeks.

Notes
[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: In this study where different regimens are being studied in each Cohort, the primary objective was to assess the safety of the different regimens and sample sizes were determined based on this. While secondary objectives were to obtain preliminary efficacy of each regimen, the intent was not to compare the regimens and as a results no statistical comparisons were made between cohorts.

End point values	Cohort A1	Cohort A2	Cohort B
Number of subjects analysed	8	3	14
Units: Number of subjects
irCR	2	0	0
irPR	2	2	7
irSD	3	1	4
irPD	1	0	1
irNonCR/Non-PD	0	0	1
Not evaluable	0	0	1

No statistical analyses for this end point

Secondary: Median Progression-free Survival (PFS) by irRECIST as Estimated Using the Kaplan-Meier Method

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End point title

Median Progression-free Survival (PFS) by irRECIST as Estimated Using the Kaplan-Meier Method

End point description

In Cohorts A1, A2 and B, PFS was measured from the date of the first dose of study treatment to the date of earliest disease progression according to irRECIST or to the date of death, if disease progression did not occur. For subjects in Cohorts C/C-FLOT and D/D2 undergoing successful surgery, post-operative PFS was measured with time origin at the day of surgery until the first occurrence of confirmed progression by irRECIST or date of death if the subject dies from any causes before progression. Per irRECIST, irPD was defined as a ≥ 20% increase from nadir in the TMTB. The median was not reached in Cohort C-FLOT, this is indicated by 999. The upper 95% confidence interval limit was not reached in Cohorts A2, C, C-FLOT and D, this has been indicated by 999.

End point type

Secondary

End point timeframe

Up to 1 year

End point values	Cohort A1	Cohort A2	Cohort B	Cohort C	Cohort C-FLOT	Cohort D/D2
Number of subjects analysed	12	5	21	11	9	14
Units: Months
median (confidence interval 95%)	8.7 (0.9 to 29.1)	5.2 (1.4 to 999)	11.9 (3.9 to 15.6)	25.40 (6.47 to 999)	32.03 (2.10 to 999)	999 (9.59 to 999)

No statistical analyses for this end point

Secondary: Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method

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End point title

Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method

End point description

After completion of treatment, all subjects were followed for survival every 6 months for up to 3 years from start of treatment. OS was measured from the date of the first dose of study treatment to the date of death or last follow-up. Subjects lost to follow-up were censored on the date when they were last known to be alive. Per protocol amendment 8.0, all post study follow-up for the collection of survival data was discontinued as of 30 June 2022. The medians were not estimable for Cohorts C, C-FLOT and D/D2, this has been indicated by a median which is indicated as 999. The upper 95% confidence interval limit was not reached in Cohorts A, A2, C, C-FLOT and D/D2, this has been indicated by 999.

End point type

Secondary

End point timeframe

Up to 30 June 2022

End point values	Cohort A1	Cohort A2	Cohort B	Cohort C	Cohort C-FLOT	Cohort D/D2
Number of subjects analysed	12	5	21	11	9	15
Units: Months
median (confidence interval 95%)	11.8 (3.1 to 999)	8.6 (2.7 to 999)	15.6 (9.3 to 33.5)	999 (18.46 to 999)	999 (8.02 to 999)	999 (13.14 to 999)

No statistical analyses for this end point

Secondary: One Year Survival Rate in Subjects with Operable OC

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End point title

One Year Survival Rate in Subjects with Operable OC ^[3]

End point description

After completion of treatment, all subjects were followed for survival every 6 months for up to 3 years from start of treatment. OS was measured from the date of the first dose of study treatment to the date of death or last follow-up. Subjects lost to follow-up were censored on the date when they were last known to be alive. Per protocol amendment 8.0, all post study follow-up for the collection of survival data was discontinued as of 30 June 2022. In Cohort C, both the upper and lower limits of the 95% confidence interval were not reached, this has been indicated by 0 and 999 respectively.

End point type

Secondary

End point timeframe

Up to 1 year

Notes
[3] - 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: In this study where different regimens are being studied in each Cohort, the primary objective was to assess the safety of the different regimens and sample sizes were determined based on this. While secondary objectives were to obtain preliminary efficacy of each regimen, the intent was not to compare the regimens and as a results no statistical comparisons were made between cohorts.

End point values	Cohort C	Cohort C-FLOT	Cohort D/D2
Number of subjects analysed	11	9	15
Units: Percent
number (confidence interval 95%)	100 (0 to 999)	89.0 (43.3 to 98.4)	86.7 (56.4 to 96.5)

No statistical analyses for this end point

Secondary: Overall Response Prior to Surgery in Operable OC (Cohorts C, C-FLOT and D/D2) using Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST)

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End point title

Overall Response Prior to Surgery in Operable OC (Cohorts C, C-FLOT and D/D2) using Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST) ^[4]

End point description

18 fluorodeoxyglucose (18F-FDG) PET scans were conducted at baseline and in Cycle 3 in Cohorts C and D, and after completion of therapy in Cohort C-FLOT and D2. Complete metabolic response: 18F-FDG–avid lesions revert to background of normal tissues in which they are located; Partial metabolic response: 30% or greater reduction in measurable tumors; Stable Metabolic Response: no visible change in metabolic activity of tumor; Progressive metabolic disease: increase in intensity or extent of tumor metabolic activity or new sites of activity. All operable OC patients in Cohorts C, C-FLOT and D/D2 who had a baseline PET scan and a PET scan prior to surgery were included in the analyses.

End point type

Secondary

End point timeframe

After completion of therapy and prior to surgery.

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: In this study where different regimens are being studied in each Cohort, the primary objective was to assess the safety of the different regimens and sample sizes were determined based on this. While secondary objectives were to obtain preliminary efficacy of each regimen, the intent was not to compare the regimens and as a results no statistical comparisons were made between cohorts.

End point values	Cohort C	Cohort C-FLOT	Cohort D/D2
Number of subjects analysed	11	6	13
Units: Subjects
Complete Metabolic Response	2	1	3
Partial Metabolic Response	5	3	7
Stable Disease	1	2	1
Progressive Disease	3	0	2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All AEs occurring between the signing of informed consent and the off-study date (i.e., through 110 days after the last dose of study treatment) were documented, regardless of a causal relationship to study drug.

Adverse event reporting additional description

AE documentation included onset/resolution dates, severity using NCI CTCAE (version 4.03), seriousness, relationship to study drug, study drug action taken, treatment and outcome. Preferred terms were counted once per subject at the maximum reported grade.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Cohort A1

Reporting group description

Metastatic/locally advanced Oesophageal Cancer, Durvalumab + Oxaliplatin/Capcitabine Chemotherapy

Reporting group title

Cohort A2

Reporting group description

Metastatic/locally advanced Oesophageal Cancer, Durvalumab, Tremelimumab + Oxaliplatin/Capcitabine Chemotherapy

Reporting group title

Cohort B

Reporting group description

Metastatic/locally advanced Oesophageal Cancer, Durvalumab, Tremelimumab + Oxaliplatin/Capcitabine Chemotherapy

Reporting group title

Cohort C

Reporting group description

Operable Oesophageal Cancer; Durvavalumab + Oxaliplatin/Capcitabine Chemotherapy

Reporting group title

Cohort C-FLOT

Reporting group description

Operable Oesophageal Cancer, Durvalumab + FLOT (5-flourouracil, leucovorin, oxaliplatin, docetaxel) Chemotherapy

Reporting group title

Cohort D/D2

Reporting group description

Operable Oesophageal Cancer, Durvalumab + Neoadjuvant Chemo(radio)therapy with Paclitaxel, Carboplatin and radiotherapy.

Serious adverse events	Cohort A1	Cohort A2	Cohort B	Cohort C	Cohort C-FLOT	Cohort D/D2
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 12 (58.33%)	4 / 5 (80.00%)	12 / 21 (57.14%)	7 / 11 (63.64%)	6 / 9 (66.67%)	10 / 15 (66.67%)
number of deaths (all causes)	9	5	16	5	2	6
number of deaths resulting from adverse events	3	2	4	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
subjects affected / exposed	2 / 12 (16.67%)	1 / 5 (20.00%)	4 / 21 (19.05%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 4	0 / 0	0 / 0	0 / 0
Vascular disorders
Embolism
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Jejunostomy refashioning
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagectomy
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Postoperative wound complication
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Encephalitis autoimmune
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	3 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	2 / 12 (16.67%)	0 / 5 (0.00%)	2 / 21 (9.52%)	1 / 11 (9.09%)	0 / 9 (0.00%)	3 / 15 (20.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 1	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Odynophagia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 12 (0.00%)	2 / 5 (40.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Tubulointerstitial nephritis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Pain in jaw
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes simplex
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	2 / 9 (22.22%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Orchitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort A1	Cohort A2	Cohort B	Cohort C	Cohort C-FLOT	Cohort D/D2
Total subjects affected by non serious adverse events
subjects affected / exposed	12 / 12 (100.00%)	5 / 5 (100.00%)	21 / 21 (100.00%)	11 / 11 (100.00%)	9 / 9 (100.00%)	15 / 15 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	2
Skin papilloma
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0
Tumour pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	1	0	0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	2	0	0	0
Flushing
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Hypotension
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	0
Orthostatic hypotension
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Phlebitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	2	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	1	0	0	0
Chest discomfort
subjects affected / exposed	1 / 12 (8.33%)	1 / 5 (20.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	3	1	1	0	0	0
Chest pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	3 / 21 (14.29%)	0 / 11 (0.00%)	1 / 9 (11.11%)	2 / 15 (13.33%)
occurrences all number	0	0	3	0	1	2
Chills
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Early satiety
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0
Fatigue
subjects affected / exposed	10 / 12 (83.33%)	5 / 5 (100.00%)	13 / 21 (61.90%)	7 / 11 (63.64%)	6 / 9 (66.67%)	8 / 15 (53.33%)
occurrences all number	16	10	23	17	11	18
Feeling cold
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	2	0	0
Influenza like illness
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	2	2	0	0	0
Infusion site reaction
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Mucosal inflammation
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	3	0	1	0
Oedema peripheral
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	0
Pain
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0
Peripheral swelling
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	2	0	0	0
Pyrexia
subjects affected / exposed	2 / 12 (16.67%)	2 / 5 (40.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	2 / 9 (22.22%)	0 / 15 (0.00%)
occurrences all number	3	2	0	0	3	0
Temperature intolerance
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	2 / 21 (9.52%)	3 / 11 (27.27%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	2	3	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 12 (33.33%)	2 / 5 (40.00%)	4 / 21 (19.05%)	6 / 11 (54.55%)	2 / 9 (22.22%)	5 / 15 (33.33%)
occurrences all number	4	2	5	6	2	6
Dyspnoea
subjects affected / exposed	2 / 12 (16.67%)	2 / 5 (40.00%)	4 / 21 (19.05%)	3 / 11 (27.27%)	1 / 9 (11.11%)	3 / 15 (20.00%)
occurrences all number	2	3	6	3	1	3
Dyspnoea exertional
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 11 (9.09%)	0 / 9 (0.00%)	2 / 15 (13.33%)
occurrences all number	1	0	1	1	0	2
Epistaxis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Laryngospasm
subjects affected / exposed	1 / 12 (8.33%)	2 / 5 (40.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	2	0	0	0	0
Nasal congestion
subjects affected / exposed	1 / 12 (8.33%)	1 / 5 (20.00%)	1 / 21 (4.76%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	2	1	1	0	2
Productive cough
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	0
Pulmonary embolism
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	2	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0
Upper-airway cough syndrome
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0
Psychiatric disorders
Depressed mood
subjects affected / exposed	0 / 12 (0.00%)	2 / 5 (40.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	2	0	0	1	0
Confusional state
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Depression
subjects affected / exposed	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	0	0	0	0
Insomnia
subjects affected / exposed	3 / 12 (25.00%)	1 / 5 (20.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)
occurrences all number	3	1	1	0	0	3
Irritability
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	4 / 21 (19.05%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	0	0	8	0	1	2
Amylase increased
subjects affected / exposed	3 / 12 (25.00%)	1 / 5 (20.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	5	1	10	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	5 / 21 (23.81%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	8	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	5	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	4	0
Blood iron decreased
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0
Blood magnesium decreased
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Blood thyroid stimulating hormone decreased
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood urea increased
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	2 / 9 (22.22%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	2	0
C-reactive protein increased
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Lipase increased
subjects affected / exposed	6 / 12 (50.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	10	0	1	0	2	0
Neutrophil count decreased
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	2	0	0	0
Platelet count decreased
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	4	0	0	0
Transaminases increased
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	5	0	4	0	0	0
Weight decreased
subjects affected / exposed	2 / 12 (16.67%)	3 / 5 (60.00%)	4 / 21 (19.05%)	2 / 11 (18.18%)	0 / 9 (0.00%)	4 / 15 (26.67%)
occurrences all number	5	3	6	3	0	8
White blood cell count decreased
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 12 (16.67%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	1	0	0	0
Dumping syndrome
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	3 / 15 (20.00%)
occurrences all number	0	0	0	0	1	4
Fall
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Infusion related reaction
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	1	0	2
Tooth fracture
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Wound complication
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	0
Wound haemorrhage
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	1	0	1
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Dizziness
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	1 / 9 (11.11%)	2 / 15 (13.33%)
occurrences all number	0	0	1	0	1	2
Dizziness postural
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	0	0	0	3	1	1
Dysaesthesia
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	3 / 21 (14.29%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	1	0	3	0	1	0
Dysgeusia
subjects affected / exposed	4 / 12 (33.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	2 / 11 (18.18%)	3 / 9 (33.33%)	1 / 15 (6.67%)
occurrences all number	4	0	0	4	3	1
Head discomfort
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Headache
subjects affected / exposed	1 / 12 (8.33%)	1 / 5 (20.00%)	2 / 21 (9.52%)	1 / 11 (9.09%)	1 / 9 (11.11%)	2 / 15 (13.33%)
occurrences all number	2	1	2	1	1	2
Lethargy
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	1	0	1
Muscle contractions involuntary
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	3 / 12 (25.00%)	2 / 5 (40.00%)	6 / 21 (28.57%)	6 / 11 (54.55%)	4 / 9 (44.44%)	0 / 15 (0.00%)
occurrences all number	6	2	10	11	6	0
Paraesthesia
subjects affected / exposed	3 / 12 (25.00%)	1 / 5 (20.00%)	3 / 21 (14.29%)	3 / 11 (27.27%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	6	1	3	3	0	0
Peripheral sensory neuropathy
subjects affected / exposed	4 / 12 (33.33%)	1 / 5 (20.00%)	5 / 21 (23.81%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	9	1	5	0	1	1
Poor quality sleep
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0
Presyncope
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	1	0	0	0
Sciatica
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0
Syncope
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	2 / 11 (18.18%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	2	0	1
Tremor
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	2	0	0	1	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 12 (41.67%)	1 / 5 (20.00%)	4 / 21 (19.05%)	0 / 11 (0.00%)	3 / 9 (33.33%)	5 / 15 (33.33%)
occurrences all number	10	6	12	0	3	6
Neutropenia
subjects affected / exposed	3 / 12 (25.00%)	1 / 5 (20.00%)	3 / 21 (14.29%)	0 / 11 (0.00%)	2 / 9 (22.22%)	3 / 15 (20.00%)
occurrences all number	9	1	9	0	3	3
Thrombocytopenia
subjects affected / exposed	4 / 12 (33.33%)	1 / 5 (20.00%)	3 / 21 (14.29%)	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)
occurrences all number	12	2	8	0	0	2
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	0
Eye disorders
Blepharospasm
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Dry eye
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Eye pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Vision blurred
subjects affected / exposed	2 / 12 (16.67%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	3	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 12 (8.33%)	2 / 5 (40.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	2	2	0	0	1
Abdominal distension
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Abdominal pain
subjects affected / exposed	4 / 12 (33.33%)	1 / 5 (20.00%)	3 / 21 (14.29%)	1 / 11 (9.09%)	1 / 9 (11.11%)	2 / 15 (13.33%)
occurrences all number	5	1	3	1	2	3
Abdominal pain lower
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	0	0	0	0	1
Abdominal pain upper
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 21 (4.76%)	2 / 11 (18.18%)	1 / 9 (11.11%)	2 / 15 (13.33%)
occurrences all number	1	0	1	2	2	2
Colitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Constipation
subjects affected / exposed	5 / 12 (41.67%)	4 / 5 (80.00%)	5 / 21 (23.81%)	1 / 11 (9.09%)	4 / 9 (44.44%)	5 / 15 (33.33%)
occurrences all number	7	5	7	1	5	5
Diarrhoea
subjects affected / exposed	7 / 12 (58.33%)	2 / 5 (40.00%)	11 / 21 (52.38%)	5 / 11 (45.45%)	7 / 9 (77.78%)	10 / 15 (66.67%)
occurrences all number	14	3	22	13	11	27
Dyspepsia
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	2 / 9 (22.22%)	4 / 15 (26.67%)
occurrences all number	0	1	0	0	4	5
Dry mouth
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	0	0	0	3	1	1
Dysphagia
subjects affected / exposed	3 / 12 (25.00%)	3 / 5 (60.00%)	4 / 21 (19.05%)	1 / 11 (9.09%)	3 / 9 (33.33%)	3 / 15 (20.00%)
occurrences all number	6	5	5	2	4	4
Epigastric discomfort
subjects affected / exposed	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	2	0	0	0	0	1
Eructation
subjects affected / exposed	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	0	0	0	0
Gastritis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	0	0	1	0	1	3
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 21 (4.76%)	4 / 11 (36.36%)	3 / 9 (33.33%)	3 / 15 (20.00%)
occurrences all number	1	0	1	5	4	4
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0
Haemorrhoids
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Melaena
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Mouth ulceration
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	1	0	0	0	1	1
Nausea
subjects affected / exposed	10 / 12 (83.33%)	4 / 5 (80.00%)	12 / 21 (57.14%)	5 / 11 (45.45%)	5 / 9 (55.56%)	9 / 15 (60.00%)
occurrences all number	17	7	24	6	6	17
Lip pruritus
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Malabsorption
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Odynophagia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Oesophageal fistula
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Oesophageal ulcer
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	0
Oesophagitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	2 / 9 (22.22%)	5 / 15 (33.33%)
occurrences all number	0	0	0	0	2	6
Oral pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	1	0	0
Pancreatitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Rectal haemorrhage
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Retching
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	0
Salivary hypersecretion
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Sensitivity of teeth
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0
Steatorrhoea
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Stomatitis
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	1	0	0	0
Tongue coated
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Vomiting
subjects affected / exposed	11 / 12 (91.67%)	2 / 5 (40.00%)	8 / 21 (38.10%)	1 / 11 (9.09%)	3 / 9 (33.33%)	6 / 15 (40.00%)
occurrences all number	15	11	14	1	3	8
Hepatobiliary disorders
Hepatitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Hyperbilirubinaemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Dermatitis acneiform
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Dermatitis psoriasiform
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Dry skin
subjects affected / exposed	2 / 12 (16.67%)	1 / 5 (20.00%)	1 / 21 (4.76%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	5	1	1	1	0	0
Erythema
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Night sweats
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	2	0	1	0	1
Onycholysis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	5 / 21 (23.81%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	2	0	8	1	0	0
Pigmentation disorder
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Pruritus
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	5 / 21 (23.81%)	2 / 11 (18.18%)	1 / 9 (11.11%)	2 / 15 (13.33%)
occurrences all number	0	0	7	2	1	4
Pruritus generalised
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	2	0	0	1
Rash
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	3 / 21 (14.29%)	0 / 11 (0.00%)	4 / 9 (44.44%)	5 / 15 (33.33%)
occurrences all number	0	1	3	0	4	6
Rash generalised
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Rash macular
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	1	0
Rash maculo-papular
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	1	0	0	0
Rash pruritic
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	1	0	0	1
Swelling face
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	0
Systemic lupus erythematosus rash
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	0	1	0	1	1	1
Hypothyroidism
subjects affected / exposed	2 / 12 (16.67%)	1 / 5 (20.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	2	1	0	1	2	2
Adrenal insufficiency
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	2 / 21 (9.52%)	1 / 11 (9.09%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	1	0	2	1	1	1
Arthritis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Back pain
subjects affected / exposed	3 / 12 (25.00%)	0 / 5 (0.00%)	2 / 21 (9.52%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	4	0	2	1	0	1
Flank pain
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Jaw disorder
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Limb discomfort
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	1	0	1
Muscle spasms
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Muscular weakness
subjects affected / exposed	1 / 12 (8.33%)	1 / 5 (20.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	2	1	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	2 / 9 (22.22%)	0 / 15 (0.00%)
occurrences all number	0	1	3	0	2	0
Musculoskeletal pain
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	2 / 15 (13.33%)
occurrences all number	1	0	0	0	3	2
Musculoskeletal stiffness
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Myalgia
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	0
Myopathy
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Osteoporosis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Pain in extremity
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	1	0	0	3	1	0
Pain in jaw
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	2	0	1	0	1
Infections and infestations
Balanitis candida
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Cellulitis
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	0	1	0	0	1
Cystitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Gastroenteritis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0
Hordeolum
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Influenza
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1	1
Localised infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	2
Lower respiratory tract infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	4 / 21 (19.05%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	4	1	0	1
Medical device site infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	2	1
Nail infection
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1
Oesophageal candidiasis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0
Oral candidiasis
subjects affected / exposed	3 / 12 (25.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 11 (9.09%)	2 / 9 (22.22%)	2 / 15 (13.33%)
occurrences all number	3	0	1	1	2	2
Oropharyngeal candidiasis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Pneumonia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	2 / 11 (18.18%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	2	0	0
Respiratory tract infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	2	0	0	0
Rhinitis
subjects affected / exposed	0 / 12 (0.00%)	2 / 5 (40.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	2	2	0	0	1
Skin infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Upper respiratory tract infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	3 / 21 (14.29%)	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)
occurrences all number	0	0	3	0	0	2
Urinary tract infection
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	2 / 11 (18.18%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	0	1	0	2	1	1
Vulvovaginal candidiasis
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Wound infection
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 12 (16.67%)	3 / 5 (60.00%)	3 / 21 (14.29%)	2 / 11 (18.18%)	5 / 9 (55.56%)	5 / 15 (33.33%)
occurrences all number	2	6	4	2	6	12
Dehydration
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1	1
Diabetes mellitus
subjects affected / exposed	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0
Gout
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0
Hyperglycaemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0
Hypoalbuminaemia
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)
occurrences all number	1	0	2	0	0	1
Hypocalcaemia
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	1	0	0	0	1	1
Hypoglycaemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0
Hypokalaemia
subjects affected / exposed	2 / 12 (16.67%)	1 / 5 (20.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	2 / 9 (22.22%)	3 / 15 (20.00%)
occurrences all number	4	1	1	0	2	3
Hypomagnesaemia
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 11 (9.09%)	1 / 9 (11.11%)	1 / 15 (6.67%)
occurrences all number	1	0	0	1	1	1
Hyponatraemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 11 (0.00%)	2 / 9 (22.22%)	0 / 15 (0.00%)
occurrences all number	0	0	2	0	2	0
Hypophosphataemia
subjects affected / exposed	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 11 (9.09%)	2 / 9 (22.22%)	2 / 15 (13.33%)
occurrences all number	1	0	1	1	2	2
Iron deficiency
subjects affected / exposed	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0

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Were there any global substantial amendments to the protocol? Yes

14 Jul 2017

Change to treatment regimen in Cohort D (neoadjuvant chemoradiotherapy before surgery in operable oesophageal cancer): The oxaliplatin-capecitabine backbone of the CRT regimen was replaced with a paclitaxel/carboplatin regimen.

08 Sep 2017

Additional requirements for carboplatin and paclitaxel treatment. Women of childbearing potential should avoid becoming pregnant while taking carboplatin and paclitaxel; they should notify the treating physician immediately if pregnancy occurs. Female and male subjects of fertile age and/or their partners should use contraceptives during and for at least 6 months after treatment with these drugs. Male subjects should also avoid sperm donation during and for at least 6 months after treatment with these drugs. Breastfeeding should be discontinued for the duration of treatment with these drugs. Male subjects should be advised regarding cryoconservation of sperm prior to treatment because of the possibility of irreversible infertility due to the treatment. CYP2C8 or CYP3A4 inhibitors/inducers: Caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of paclitaxel may be increased due to higher paclitaxel exposure. Administering paclitaxel concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because efficacy may be compromised because of lower paclitaxel exposures. Nephrotoxic/ototoxic drugs: Auditory defects have been reported during carboplatin therapy. Concurrent therapy with nephrotoxic drugs or ototoxic drugs such as aminoglycosides, vancomycin, capreomycin and diuretics is not recommended as they may increase or exacerbate toxicity, particularly in renal failure patients, due to carboplatin induced changes in renal clearance.

10 Mar 2018

The eligbility criteria have been amended to exclude patients who have received prior full dose chemotherapy, this enables collection of a pre-treatment biopsy for the planned biomarker analysis (tertiary endpoint). This eligibility criteria was originally included in the protocol and was removed from the protocol in error during a previous protocol amendment. Elevations of amylase and lipase are expected adverse events for durvalumab or the combination of durvalumab and tremelimumab and the study requires regular testing of both as potential indicators of pancreatitis. The dose limiting toxicity definitions have been clarified to exclude grade 3+ asymptomatic increases in amylase or lipase, which show no clinical evidence of pancreatitis. Grade 3+ pancreatitis remains a dose limiting toxicity. Expected adverse events have been added to the protocol, based on the durvalumab and tremelimumab dose modifications guidelines (updated Nov 2017). The events added are myocarditis (previously listed under 'other inflammatory responses'), myositis/polymyositis and some new events added to 'other inflammatory responses'. Clarification has been added to indicate that surgery timing is according to institutional policies. The study was initially set-up as a single site study and the 6-8 weeks post treatment timeframe for surgery was as per standard of care at that site alone. Surgery may be delayed at any site as per clinical need.

20 Jul 2018

The chemotherapy backbone administered in Cohort C was updated due to changes in standard of care treatment in the UK. The new cohort was referred to as Cohort C-FLOT which is a regimen combining 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and docetaxel. Based on emerging data, a proposal was made to add Cohort C-FLOT to the study, in addition to Cohort C. The proposal for Cohort C-FLOT includes the following: 1. Replace Oxaliplatin and capecitabine as neoadjuvant chemotherapy with the FLOT regimen to run concurrently with durvalumab treatment. 2. Introduce post-operative chemotherapy, also with FLOT. This will run concurrently with durvalumab immunotherapy. 3. Subjects allocated to oxaliplatin and capecitabine in Cohort C before the introduction of Cohort C-FLOT will not be replaced and will be included in the total 20 Subjects for Cohort C + Cohort C-FLOT. The protocol will now include the collection of saliva samples for translational research at the same time point as the research biopsy (3 timepoints, baseline, immunotherapy only D22 and at end of treatment/day of surgery). Patients will be asked to consent to use of photographs of their alimentary tract taken during the biopsy procedure. Videos are taken as standard of care of the biopsy for quality improvement and still pictures may also be taken as part of this procedure. These pictures will not be identifiable. Current patients may also be reconsented. This is an optional consent.

26 Apr 2019

The Investigator(s) had the option to approach subjects with long-term survival (PFS > 1 year, still in remission) from the metastatic cohorts (A and B) of the trial to request blood (up to 300 mL) for additional testing. Introduction of Cohort D2 Cohort D2 is a subset of Cohort D subjects for whom durvalumab doses will continue during chemoradiotherapy, after the initial 4-week immunotherapy period. Enrollment was to proceed to Cohort D2, unless there was a medical reason to enroll a specific subject to Cohort D.

11 Jan 2022

The Post Study Follow-up for the collection of survival data was discontinued as of 30 June 2022. As of 30 June 2022, all subjects had completed treatment and On Study Follow-up and all but up to 8 subjects had completed the 3-year Post Study Follow-up, which would have occurred by December 2022 for the remaining subjects.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results:
Phase 1/2 Study of anti-PD-L1 in Combination with Chemo(radio)therapy for Oesophageal Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects With Best Overall Tumor Response by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)

Primary: Number of Subjects With Best Overall Tumor Response by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)

Secondary: Number of Subjects With Metastatic/locally Advanced Oesophageal Cancer (OC) Who Had a Response at Cycle 6 by irRECIST

Secondary: Number of Subjects With Metastatic/locally Advanced Oesophageal Cancer (OC) Who Had a Response at Cycle 6 by irRECIST

Secondary: Median Progression-free Survival (PFS) by irRECIST as Estimated Using the Kaplan-Meier Method

Secondary: Median Progression-free Survival (PFS) by irRECIST as Estimated Using the Kaplan-Meier Method

Secondary: Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method

Secondary: Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method

Secondary: One Year Survival Rate in Subjects with Operable OC

Secondary: One Year Survival Rate in Subjects with Operable OC

Secondary: Overall Response Prior to Surgery in Operable OC (Cohorts C, C-FLOT and D/D2) using Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST)

Secondary: Overall Response Prior to Surgery in Operable OC (Cohorts C, C-FLOT and D/D2) using Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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Outside EU/EEA

Clinical trials

Clinical Trial Results: Phase 1/2 Study of anti-PD-L1 in Combination with Chemo(radio)therapy for Oesophageal Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects With Best Overall Tumor Response by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)

Primary: Number of Subjects With Best Overall Tumor Response by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)

Secondary: Number of Subjects With Metastatic/locally Advanced Oesophageal Cancer (OC) Who Had a Response at Cycle 6 by irRECIST

Secondary: Number of Subjects With Metastatic/locally Advanced Oesophageal Cancer (OC) Who Had a Response at Cycle 6 by irRECIST

Secondary: Median Progression-free Survival (PFS) by irRECIST as Estimated Using the Kaplan-Meier Method

Secondary: Median Progression-free Survival (PFS) by irRECIST as Estimated Using the Kaplan-Meier Method

Secondary: Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method

Secondary: Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method

Secondary: One Year Survival Rate in Subjects with Operable OC

Secondary: One Year Survival Rate in Subjects with Operable OC

Secondary: Overall Response Prior to Surgery in Operable OC (Cohorts C, C-FLOT and D/D2) using Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST)

Secondary: Overall Response Prior to Surgery in Operable OC (Cohorts C, C-FLOT and D/D2) using Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Phase 1/2 Study of anti-PD-L1 in Combination with Chemo(radio)therapy for Oesophageal Cancer