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Clinical Trial Results:
A Phase Ib/II, Open-label, Multicenter Study of Novel Oncology Therapies in Combination with Chemotherapy and Bevacizumab as First-line Therapy in Metastatic Microsatellite-stable Colorectal Cancer (COLUMBIA-1)

Summary
EudraCT number	2019-000974-44
Trial protocol	ES
Global end of trial date	10 Oct 2022

Results information
Results version number	v1(current)
This version publication date	22 Oct 2023
First version publication date	22 Oct 2023
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

D910CC00001

ISRCTN number

US NCT number

NCT04068610

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca Clinical study Information Center

Sponsor organisation address

One MedImmune Way, Gaithersburg, Maryland, United States, 20878

Public contact

Global Clinical Lead, AstraZeneca Clinical study Information Center, +1 8772409479, information.center@astrazeneca.com

Scientific contact

Global Clinical Lead, AstraZeneca Clinical study Information Center, +1 8772409479, information.center@astrazeneca.com

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

19 May 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Oct 2022

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objectives of the study are: 1. Part 1: To evaluate the safety and tolerability profile of FOLFOX (oxaliplatin, folinic acid, fluorouracil [5-FU]) + bevacizumab + novel oncology therapy combinations. 2. Part 2: To compare the efficacy of FOLFOX + bevacizumab + novel oncology therapy combinations versus FOLFOX + bevacizumab.

Protection of trial subjects

The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Participants signed an informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Sep 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 6

Country: Number of subjects enrolled

Canada: 3

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Spain: 7

Country: Number of subjects enrolled

United States: 39

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

The study was conducted at study sites located in Australia, Canada, France, Spain, and United States.

Screening details

A total of 61 participants were randomized in this study of which 59 participants received treatment.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

Arm description

Participants in Part 1 safety run-in arm (S1) received intravenous (IV) infusions of FOLFOX (5-fluorouracil [5-FU]: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2,) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg every 4 weeks (Q4W) and IV oleclumab 3000 mg every 2 weeks (Q2W) till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

MEDI4736

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion of durvalumab 1500 mg Q4W until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion of bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.

Investigational medicinal product name

FOLFOX

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion of FOLFOX (5-FU: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2 on Day 1 of every Cycle [14-day cycle]) until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.

Investigational medicinal product name

Oleclumab

Investigational medicinal product code

MEDI9447

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion of oleclumab 3000 mg Q2W till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.

Part 2 (C1): FOLFOX + Bevacizumab

Arm description

Participants in Part 2 control 1 arm (C1) received IV infusions of FOLFOX (5-FU: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2) in combination with IV bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.

Arm type

Experimental

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

FOLFOX

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

Arm description

Participants in Part 2 experimental 1 arm (E1) received IV infusions of FOLFOX (5-FU: 2400 mg/m^2 over 46-48 hours [Day 1 and 2 of every 14-day Cycle], oxaliplatin: 85 mg/m^2, folinic acid: 400 mg/m^2) and bevacizumab 5 mg/kg on Day 1 of every Cycle (14-day cycle) in combination with IV durvalumab 1500 mg Q4W and IV oleclumab 3000 mg Q2W till 4 doses (Cycle 4) then Q4W starting on Cycle 5 Day 1 until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

MEDI4736

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion of durvalumab 1500 mg Q4W until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

FOLFOX

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Oleclumab

Investigational medicinal product code

MEDI9447

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 1	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab	Part 2 (C1): FOLFOX + Bevacizumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Started	7	26	26
Completed	0	0	0
Not completed	7	26	26
Adverse event, serious fatal	-	1	3
Consent withdrawn by subject	-	4	2
Death	4	7	10
Unspecified	3	12	11
Lost to follow-up	-	2	-

Baseline characteristics

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Reporting group title

Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

Reporting group description

Reporting group title

Part 2 (C1): FOLFOX + Bevacizumab

Reporting group description

Reporting group title

Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

Reporting group description

Reporting group values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab	Part 2 (C1): FOLFOX + Bevacizumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab	Total
Number of subjects	7	26	26	59
Age categorical
Units: Participants
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	4	18	15	37
From 65-84 years	3	8	11	22
85 years and over	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	59.4 ± 12.4	55.5 ± 13.5	59.8 ± 12.5	-
Sex: Female, Male
Units: Participants
Female	3	7	11	21
Male	4	19	15	38
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0
Asian	0	1	2	3
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	0	1	0	1
White	7	20	23	50
More than one race	0	0	0	0
Unknown or Not Reported	0	4	1	5
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	4	1	5
Not Hispanic or Latino	7	19	23	49
Unknown or Not Reported	0	3	2	5

End points

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Reporting group title

Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

Reporting group description

Reporting group title

Part 2 (C1): FOLFOX + Bevacizumab

Reporting group description

Reporting group title

Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

Reporting group description

Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part 1

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End point title

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part 1 ^[1] ^[2]

End point description

An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.

End point type

Primary

End point timeframe

Day 1 through 90 days after the last dose of study drug (approximately 2.8 years)

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: 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.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7
Units: Participants
Any TEAE	7
Any TESAE	1

No statistical analyses for this end point

Primary: Number of Participants With Dose Limiting Toxicities (DLTs) in Part 1

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End point title

Number of Participants With Dose Limiting Toxicities (DLTs) in Part 1 ^[3] ^[4]

End point description

DLT:Any study drug related Grade (G)3/higher toxicity including: G3/G4 immune-mediated AE, G3/4 noninfectious pneumonitis/colitis, transaminase elevation (TE) >8x upper limit of normal (ULN)/total bilirubin (TBL) >5xULN, increase in AST/ALT >=3xULN plus TBL >=2xULN, isolated liver TE >5 but =<8xULN/isolated TBL >3 but =<5xULN not downgrading to <=G1 within 14 days (D) of onset, G3 nausea/vomiting/diarrhea not resolving to <=G2 within 3D of supportive care, G3/4 febrile neutropenia, G3/4 neutropenia not associated with fever/systemic infection, anemia (G4,G3 with clinical sequelae/requires >2 units of RBC transfusion, thrombocytopenia (G4, G3 that did not improve by at least 1 G within 7D, G3/4 associated with >=G3 hemorrhage). DLT evaluable population: participants in Part 1 safety run-in who received full dose of durvalumab and ≥75% of number of doses of FOLFOX+bevacizumab+other novel oncology therapy and completed safety follow-up through DLT evaluation period/experienced any DLT.

End point type

Primary

End point timeframe

From Day 1 to 28 days after the first dose of novel oncology therapy (durvalumab and oleclumab)

Notes
[3] - 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: 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.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7
Units: Participants	0

No statistical analyses for this end point

Primary: Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1

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End point title

Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1 ^[5] ^[6]

End point description

Number of participants with at least common terminology criteria for adverse events (CTCAE v5.0) 2-grade shift from baseline (last assessment prior to first dose) to worst toxicity grade in clinical laboratory parameters are reported. Clinical laboratory parameter analysis included hematology, clinical chemistry, coagulation, and urinalysis. As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.

End point type

Primary

End point timeframe

Baseline (Day 1) through 90 days after the last dose of study drug (approximately 2.8 years)

Notes
[5] - 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: 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.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7
Units: Participants
Hemoglobin (Hypo)	1
Lymphocytes (Hypo)	2
Neutrophils	4
Leukocytes (Hypo)	3
Activated partial thromboplastin time	1
Albumin	1
Amylase	2
Bilirubin	1
Calcium corrected (Hypo)	1
Creatine kinase	2
Creatinine	1
Gamma glutamyl transferase	1
Glucose	1
Lipase	5
Magnesium (Hyper)	1
Magnesium (Hypo)	1

No statistical analyses for this end point

Primary: Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 1

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End point title

Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 1 ^[7] ^[8]

End point description

Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (body temperature, blood pressure, and pulse rate). As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.

End point type

Primary

End point timeframe

Day 1 through 90 days after the last dose of study drug (approximately 2.8 years)

Notes
[7] - 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: 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.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7
Units: Participants
Pyrexia	2
Temperature intolerance	1
Hypertension	3

No statistical analyses for this end point

Primary: Percentage of Participants With Objective Response (OR) per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) in Part 2

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End point title

Percentage of Participants With Objective Response (OR) per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) in Part 2 ^[9]

End point description

The OR is defined as best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) based on RECIST v1.1 criteria. The CR is defined as disappearance of all target lesions (TLs) and non-target lesions (NTLs), normalization of tumor marker level, any pathological lymph nodes (target and non-target) must have reduction in short axis < 10 mm, and no new lesion. The PR is defined as at least a 30% decrease in the sum of the diameters (SoD) of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. Intent-to-treat (ITT) population included participants who received any study drug and were analyzed according to the treatment group they were randomized to. In Part 2, randomization occurred between Day -8 and the same date as dosing.

End point type

Primary

End point timeframe

Randomization through end of study (approximately 2.6 years)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 2 (C1): FOLFOX + Bevacizumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	26	26
Units: Percentage of Participants
number (confidence interval 95%)	46.2 (26.6 to 66.6)	61.5 (40.6 to 79.8)

Statistical Analysis 1

Comparison groups

Part 2 (C1): FOLFOX + Bevacizumab v Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3173

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

5.6

Secondary: Percentage of Participants With OR per RECIST v1.1 in Part 1

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End point title

Percentage of Participants With OR per RECIST v1.1 in Part 1 ^[10]

End point description

The OR is defined as BOR of confirmed CR or confirmed PR based on RECIST v1.1 criteria. The CR is defined as disappearance of all TLs and NTLs, normalization of tumor marker level, any pathological lymph nodes (target and non-target) must have reduction in short axis < 10 mm, and no new lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.

End point type

Secondary

End point timeframe

First dose (Day 1) through end of study (approximately 2.8 years)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7
Units: Percentage of Participants
number (confidence interval 95%)	71.4 (29.0 to 96.3)

No statistical analyses for this end point

Secondary: Best Overall Response (BOR) per RECIST v1.1 in Part 1

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End point title

Best Overall Response (BOR) per RECIST v1.1 in Part 1 ^[11]

End point description

BOR: best response including CR, PR, stable disease (SD), progressive disease (PD), and non-evaluable (NE) among all overall responses per RECIST v1.1 application to investigator assessments. CR: disappearance of all TLs and NTLs, any pathological lymph nodes (target, non-target) must have reduction in short axis <10mm, and no new lesions. PR: at least 30% decrease in SoD of TL (compared to baseline) and no new NTL. Confirmation of CR and PR is required after 4 weeks. PD: at least 20% increase in SoDs of TLs, or unequivocal progression of existing NTL, or new lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD in at least 8 weeks from first dose of study drug. NE: either when no or only subset of lesion measurements are made at an assessment. Number of participants with BOR are reported. As-treated population: participants who received any study drugs and were analyzed according to the treatment they actually received.

End point type

Secondary

End point timeframe

First dose (Day 1) through end of study (approximately 2.8 years)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7
Units: Participants
CR	0
PR	5
SD >=8 weeks	2
PD	0
NE	0

No statistical analyses for this end point

Secondary: Percentage of Participants with Disease Control (DC) per RECIST v1.1 in Part 1

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End point title

Percentage of Participants with Disease Control (DC) per RECIST v1.1 in Part 1 ^[12]

End point description

The DC is defined as BOR of confirmed CR, confirmed PR, or stable disease (SD; maintained for ≥ 16 weeks) per RECIST v1.1. The CR is defined as disappearance of all TLs and NTLs, normalization of tumor marker level, any pathological lymph nodes (target and non-target) must have reduction in short axis < 10 mm, and no new lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesion. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Participants with SD will be included in the DC if they maintain SD for >= 16 weeks from start of treatment. As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.

End point type

Secondary

End point timeframe

First dose (Day 1) through end of study (approximately 2.8 years)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7
Units: Percentage of Participants
number (confidence interval 95%)	100 (59.0 to 100)

No statistical analyses for this end point

Secondary: Percentage of Participants with PFS at 12 months (PFS-12) per RECIST v1.1 in Part 1

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End point title

Percentage of Participants with PFS at 12 months (PFS-12) per RECIST v1.1 in Part 1 ^[13]

End point description

The PFS is defined as the time from assignment until the first documentation of PD or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer therapy prior to progression. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The PFS was analyzed using Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. The percentage of participants progression free and alive at 12 months (PFS-12) are reported. As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received. Assignment occurred between Day -3 and -1.

End point type

Secondary

End point timeframe

Assignment through 12 months

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7
Units: Percentage of Participants
number (confidence interval 95%)	28.6 (4.1 to 61.2)

No statistical analyses for this end point

Secondary: Overall Survival (OS) per RECIST v1.1 in Part 1

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End point title

Overall Survival (OS) per RECIST v1.1 in Part 1 ^[14]

End point description

The OS is defined as the time from first dose until death due to any cause. The overall survival was analyzed using the Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received. The arbitrary number 99999 signified the data for upper limit of CI could not be derived due to insufficient events being observed.

End point type

Secondary

End point timeframe

First dose (Day 1) through end of study (approximately 2.8 years)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7
Units: Months
median (confidence interval 95%)	30.1 (11.9 to 99999)

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS) per RECIST v1.1 in Part 1

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End point title

Progression-Free Survival (PFS) per RECIST v1.1 in Part 1 ^[15]

End point description

The PFS is defined as the time from assignment until the first documentation of PD or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer therapy prior to progression. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The PFS was analyzed using the Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received. Assignment occurred between Day -3 and -1.

End point type

Secondary

End point timeframe

Assignment through end of study (approximately 2.8 years)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7
Units: Months
median (confidence interval 95%)	9.5 (7.8 to 18.2)

No statistical analyses for this end point

Secondary: Duration of Response (DoR) per RECIST v1.1 in Part 1

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End point title

Duration of Response (DoR) per RECIST v1.1 in Part 1 ^[16]

End point description

DoR: time from the first documentation of a confirmed response (CR/PR) until first documentation of PD/death due to any cause, whichever occurs first. CR: disappearance of all TLs and NTLs, normalization of tumor marker level, any pathological lymph nodes (target and non-target) must have reduction in short axis <10mm, and no new lesions. PR: at least 30% decrease in the SoD of TLs (compared to baseline) and no new lesion. Confirmation of CR and PR is required after 4 weeks. PD: at least 20% increase in SoDs of TLs (reference the smallest sum on study and increase of at least 5mm), or unequivocal progression of existing NTL/new lesions. The DoR was analyzed using Kaplan-Meier method and was assessed for those participants who had OR. As-treated population: participants who received any study drugs and were analyzed according to received treatment. Arbitrary number 99999 signified upper limit confidence interval (CI) could not be derived as insufficient number of participants had DoR.

End point type

Secondary

End point timeframe

First dose (Day 1) through end of study (approximately 2.8 years)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	5
Units: Months
median (confidence interval 95%)	6.0 (5.5 to 99999)

No statistical analyses for this end point

Secondary: Number of Participants With TEAEs and TESAEs in Part 2

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End point title

Number of Participants With TEAEs and TESAEs in Part 2 ^[17]

End point description

An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.

End point type

Secondary

End point timeframe

Day 1 through 90 days after the last dose of study drug (approximately 2.6 years)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 2 (C1): FOLFOX + Bevacizumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	26	26
Units: Participants
Any TEAE	26	26
Any TESAE	7	12

No statistical analyses for this end point

Secondary: Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2

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End point title

Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2 ^[18]

End point description

Number of participants with at least CTCAE v5.0 2-grade shift from baseline (last assessment prior to first dose) to worst toxicity grade in clinical laboratory parameters are reported. Clinical laboratory parameter analysis included hematology, clinical chemistry, coagulation, and urinalysis. As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received. Here, number analyzed (n) denotes number of participants analyzed for the specified parameter.

End point type

Secondary

End point timeframe

Baseline (Day 1) through 90 days after the last dose of study drug (approximately 2.6 years)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 2 (C1): FOLFOX + Bevacizumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	26	26
Units: Participants
Hemoglobin (Hypo)	0	1
Lymphocytes (Hyper)	0	2
Lymphocytes (Hypo)	3	6
Neutrophils	7	8
Platelets	3	2
Leukocytes (Hypo)	2	4
Activated partial thromboplastin time	5	5
Albumin	0	3
Alkaline phosphatase	1	1
Alanine aminotransferase	2	1
Amylase	7	3
Aspartate aminotransferase	1	0
Bilirubin	1	1
Calcium corrected (Hypo)	0	1
Creatine kinase (n=25, 26)	2	3
Creatinine	2	2
Gamma glutamyl transferase (n=26,25)	5	4
Potassium (Hyper)	0	2
Potassium (Hypo)	0	2
Lipase	12	15
Magnesium (Hypo)	0	1
Sodium (Hypo)	2	2

No statistical analyses for this end point

Secondary: Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2

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End point title

Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 ^[19]

End point description

End point type

Secondary

End point timeframe

Day 1 through 90 days after the last dose of study drug (approximately 2.6 years)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 2 (C1): FOLFOX + Bevacizumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	26	26
Units: Participants
Pyrexia	3	5
Temperature intolerance	5	5
Hypertension	4	4
Hypotension	1	1
Supraventricular tachycardia	1	0
Ventricular tachycardia	1	0

No statistical analyses for this end point

Secondary: BOR per RECIST v1.1 in Part 2

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End point title

BOR per RECIST v1.1 in Part 2 ^[20]

End point description

BOR: best response including CR, PR, SD, PD, NE among all overall responses per RECIST v1.1 application to investigator assessments. CR: disappearance of all TLs and NTLs, any pathological lymph nodes (target, non-target) must have reduction in short axis <10mm, no new lesions. PR: at least 30% decrease in SoD of TL, no new NTL. Confirmation of CR, PR is required after 4 weeks. PD: at least 20% increase in SoDs of TLs (reference the smallest sum on study and increase of at least 5mm), or unequivocal progression of existing NTL, or new lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD in at least 8 weeks from first dose of study drug. NE: either when no or only subset of lesion measurements are made at an assessment. Number of participants with BOR are reported. ITT population: participants who received any study drug and were analyzed according randomized treatment. Randomization occurred between Day -8 and the same date as dosing.

End point type

Secondary

End point timeframe

Randomization through end of study (approximately 2.6 years)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: 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.

End point values	Part 2 (C1): FOLFOX + Bevacizumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	26	26
Units: Participants
CR	0	1
PR	12	15
SD >=8 weeks	11	6
PD	1	3
NE	2	1

No statistical analyses for this end point

Secondary: PFS per RECIST v1.1 in Part 2

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End point title

PFS per RECIST v1.1 in Part 2 ^[21]

End point description

The PFS is defined as the time from randomization until the first documentation of PD or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer therapy prior to progression. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The PFS was analyzed using the Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. The ITT population included participants who received any study drug and were analyzed according to the treatment group they were randomized to. In Part 2, randomization occurred between Day -8 and the same date as dosing.

End point type

Secondary

End point timeframe

Randomization through end of study (approximately 2.6 years)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: 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.

End point values	Part 2 (C1): FOLFOX + Bevacizumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	26	26
Units: Months
median (confidence interval 95%)	11.1 (7.3 to 16.2)	10.9 (6.9 to 15.1)

No statistical analyses for this end point

Secondary: Percentage of Participants with DC per RECIST v1.1 in Part 2

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End point title

Percentage of Participants with DC per RECIST v1.1 in Part 2 ^[22]

End point description

The DC is defined as BOR of confirmed CR, confirmed PR, or SD (maintained for ≥ 16 weeks) per RECIST v1.1. The CR is defined as disappearance of all TLs and NTLs, normalization of tumor marker level, any pathological lymph nodes (target and non-target) must have reduction in short axis < 10 mm, and no new lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesion. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Participants with SD will be included in the DC if they maintain SD for >= 16 weeks from start of treatment. The ITT population included participants who received any study drug and were analyzed according to the treatment group they were randomized to. In Part 2, randomization occurred between Day -8 and the same date as dosing.

End point type

Secondary

End point timeframe

Randomization through end of study (approximately 2.6 years)

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 2 (C1): FOLFOX + Bevacizumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	26	26
Units: Percentage of Participants
number (confidence interval 95%)	88.5 (69.8 to 97.6)	84.6 (65.1 to 95.6)

No statistical analyses for this end point

Secondary: DoR per RECIST v1.1 in Part 2

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End point title

DoR per RECIST v1.1 in Part 2 ^[23]

End point description

DoR: time from first documentation of confirmed response (CR/PR) until first documentation of PD/death due to any cause, whichever occurs first. CR: disappearance of all TLs, NTLs, normalization of tumor marker level, any pathological lymph nodes (target, non-target) must have reduction in short axis <10mm, no new lesions. PR: at least 30% decrease in the SoD of TLs, no new lesion. Confirmation of CR and PR is required after 4 weeks. PD: at least 20% increase in SoDs of TLs (reference smallest sum on study and increase of at least 5mm), or unequivocal progression of existing NTL, or new lesions. The DoR was analyzed using Kaplan-Meier method. ITT population: participants who received any study drug and were analyzed according to randomized treatment. DoR was assessed for only those participants who had OR. Arbitrary number 99999 signified upper limit CI could not be derived due to insufficient events being observed. Randomization occurred between Day -8 and the same date as dosing.

End point type

Secondary

End point timeframe

Randomization through end of study (approximately 2.6 years)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: 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.

End point values	Part 2 (C1): FOLFOX + Bevacizumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	12	16
Units: Months
median (confidence interval 95%)	7.7 (4.6 to 15.4)	10.3 (5.8 to 99999)

No statistical analyses for this end point

Secondary: Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1)

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End point title

Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1) ^[24]

End point description

Serum concentrations of durvalumab collected over time in Part 1 and Part 2 (E1) are reported. The lower limit of quantification (LLOQ) for durvalumab was considered to be 50 ng/mL. Pharmacokinetic (PK) evaluable population included participants who received at least 1 dose of any study drug with at least 1 reportable PK concentration. Here, number of subjects analyzed denotes those participants who were analyzed for this endpoint. Number analyzed (n) denotes those participants who had adequate serum samples. The arbitrary numbers 999.99 and 99.999 signified geometric mean and geometric CV%, respectively, were not reported as the concentration was below the LLOQ. The arbitrary number 9999999 denotes data was not reported as no participants were analyzed for the specified time point.

End point type

Secondary

End point timeframe

Part 1: Pre-dose on Day 1 of Cycle 1, 3, 7, 13; Part 2 (E1): Pre-dose on Day 1 of Cycle 1, 3, 7, 13, and 27

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7	21
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n=4,21)	999.99 ± 99.999	999.99 ± 99.999
Cycle 3 Day 1 (n=6,18)	67980 ± 20.31	48600 ± 39.67
Cycle 7 Day 1 (n=7,18)	112500 ± 28.63	97610 ± 46.56
Cycle 13 Day 1 (n=4,14)	101500 ± 30.22	147000 ± 30.57
Cycle 27 Day 1 (n=0,5)	9999999 ± 9999999	120700 ± 29.83

No statistical analyses for this end point

Secondary: OS per RECIST v1.1 in Part 2

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End point title

OS per RECIST v1.1 in Part 2 ^[25]

End point description

The OS is defined as the time from randomization until death due to any cause. The overall survival was analyzed using the Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. The ITT population included participants who received any study drug and were analyzed according to the treatment group they were randomized to. The arbitrary number 99999 and 99.999 signified the data for upper limit of CI and median could not be derived because an insufficient number of participants had event. In Part 2, randomization occurred between Day -8 and the same date as dosing.

End point type

Secondary

End point timeframe

Randomization through end of study (approximately 2.6 years)

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 2 (C1): FOLFOX + Bevacizumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	26	26
Units: Months
median (confidence interval 95%)	99.999 (20.6 to 99999)	22.4 (10.6 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants with PFS at 12 months (PFS-12) per RECIST v1.1 in Part 2

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End point title

Percentage of Participants with PFS at 12 months (PFS-12) per RECIST v1.1 in Part 2 ^[26]

End point description

The PFS is defined as the time from randomization until the first documentation of PD or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer therapy prior to progression. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm, or unequivocal progression of existing NTL, or new lesions. The PFS was analyzed using Kaplan-Meier method based on application of RECIST v1.1 to investigator assessments. The percentage of participants progression free and alive at 12 months (PFS-12) are reported. The ITT population included participants who received any study drug and were analyzed according to the treatment group they were randomized to. In Part 2, randomization occurred between Day -8 and the same date as dosing.

End point type

Secondary

End point timeframe

Randomization through 12 months

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: 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.

End point values	Part 2 (C1): FOLFOX + Bevacizumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	26	26
Units: Percentage of Participants
number (confidence interval 95%)	38.6 (18.6 to 58.3)	36.1 (17.1 to 55.5)

No statistical analyses for this end point

Secondary: Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1)

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End point title

Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1) ^[27]

End point description

Serum concentrations of oleclumab collected over time in Part 1 and Part 2 (E1) are reported. The LLOQ for oleclumab was considered to be 1 µg/mL. The PK evaluable population included participants who received at least 1 dose of any study drug with at least 1 reportable PK concentration. Here, number of subjects analyzed denotes those participants who were analyzed for this endpoint. Number analyzed (n) denotes those participants who had adequate serum samples. The arbitrary numbers 999.99 and 99.999 signified geometric mean and geometric CV%, respectively, were not reported as the concentration was below the LLOQ. The arbitrary number 9999 denotes data was not reported as no participants were analyzed for the specified time point.

End point type

Secondary

End point timeframe

Part 1: Pre-dose on Day 1 of Cycle 1, 2, 7, and 13; Part 2 (E1): Pre-dose on Day 1 of Cycle 1, 2, 7, 13, and 27

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7	22
Units: µg/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n=7,22)	999.99 ± 99.999	999.99 ± 99.999
Cycle 2 Day 1 (n=6,19)	111.2 ± 25.38	69.81 ± 199.1
Cycle 7 Day 1 (n=7,19)	186.5 ± 53.45	159.8 ± 81.62
Cycle 13 Day 1 (n=4,14)	146.7 ± 24.43	170.1 ± 35.77
Cycle 27 Day 1 (n=0,5)	9999 ± 9999	107.9 ± 30.42

No statistical analyses for this end point

Secondary: Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1)

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End point title

Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) ^[28]

End point description

Number of participants with positive ADA to durvalumab in Part 1 (S1) and Part 2 (E1) are reported. The ADA evaluable population included all participants who received at least 1 dose of any study drug, who have a non-missing baseline ADA result and at least 1 non-missing post-baseline ADA result. Number of subjects analyzed denotes the number of participants analyzed for this endpoint. Number analyzed (n) denotes those participants who had adequate ADA sample. The arbitrary number 9999 denotes data was not reported as no participants were analyzed for the specified time point.

End point type

Secondary

End point timeframe

Part 1: Pre-dose on Day(D)1 of Cycles(C)1 (baseline [BL]), 3, 7, 13, and 90 days post last dose of study drug (approximately 2.8 years); Part 2(E1):Pre-dose on D1 of C1 (BL), 3, 7, 13, 27, and 90 days post last dose of study drug (approximately 2.6 years)

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7	20
Units: Participants
ADA positive at baseline (n=7,20)	0	2
ADA positive at Cycle 3 Day 1 (n=7,16)	0	1
ADA positive at Cycle 7 Day 1 (n=7,18)	0	0
ADA positive at Cycle 13 Day 1 (n=4,13)	0	0
ADA positive at Cycle 27 Day 1 (n=0,5)	9999	0
ADA positive at 90 days post last dose (n=4,7)	0	0

No statistical analyses for this end point

Secondary: Serum Concentrations of Bevacizumab in Part 1 (S1)

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End point title

Serum Concentrations of Bevacizumab in Part 1 (S1) ^[29]

End point description

Serum concentrations of bevacizumab collected over time in Part 1 are reported. The LLOQ for bevacizumab was considered to be 500 ng/mL. The PK evaluable population included participants who received at least 1 dose of any study drug with at least 1 reportable PK concentration. Here, number analyzed denotes those participants who had adequate serum samples. The arbitrary numbers 999.99 and 99.999 signified geometric mean and geometric CV%, respectively were not reported as the concentration was below the LLOQ.

End point type

Secondary

End point timeframe

Pre-dose on Day 1 of Cycle 1, 2, 7, 13, and 27

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n=7)	999.99 ± 99.999
Cycle 2 Day 1 (n=6)	36090 ± 16.55
Cycle 7 Day 1 (n=7)	73350 ± 39.94
Cycle 13 Day 1 (n=5)	70370 ± 30.52
Cycle 27 Day 1 (n=1)	999.99 ± 99.999

No statistical analyses for this end point

Secondary: Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1)

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End point title

Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1) ^[30]

End point description

Number of participants with positive ADA to oleclumab in Part 1 (S1) and Part 2 (E1) are reported. The ADA evaluable population included all participants who received at least 1 dose of any study drug, who have a non-missing baseline ADA result and at least 1 non-missing post-baseline ADA result. Number of subjects analyzed denotes the number of participants analyzed for this endpoint. Number analyzed (n) denotes those participants who had adequate ADA sample. The arbitrary number 9999 denotes data was not reported as no participants were analyzed for the specified time point.

End point type

Secondary

End point timeframe

Part 1: Pre-dose on D1 of C1 (BL), 2, 7, 13, and 90 days post last dose of study drug (approximately 2.8 years); Part 2 (E1): Pre-dose on D1 of C1 (BL), 2, 7, 13, 27, and 90 days post last dose of study drug (approximately 2.6 years)

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab	Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7	21
Units: Participants
ADA positive at baseline (n=7,21)	0	0
ADA positive at Cycle 2 Day 1 (n=6,17)	0	2
ADA positive at Cycle 7 Day 1 (n=7,18)	0	0
ADA positive at Cycle 13 Day 1 (n=4,13)	0	0
ADA positive at Cycle 27 Day 1 (n=0,5)	9999	0
ADA positive at 90 days post last dose (n=4,7)	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Positive ADA to Bevacizumab in Part 1 (S1)

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End point title

Number of Participants With Positive ADA to Bevacizumab in Part 1 (S1) ^[31]

End point description

Number of participants with positive ADA to bevacizumab in Part 1 (S1) are reported. The ADA evaluable population included all participants who received at least 1 dose of any study drug, who have a non-missing baseline ADA result and at least 1 non-missing post-baseline ADA result. Here, number analyzed (n) denotes those participants who had adequate ADA sample. Number of subjects analyzed denotes the number of participants analyzed for this endpoint. Number analyzed (n) denotes those participants who had adequate ADA sample.

End point type

Secondary

End point timeframe

Pre-dose on D1 of C1 (BL), 2, 7, 13, 27, and 90 days post last dose of study drug (approximately 2.8 years)

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 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.

End point values	Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
Number of subjects analysed	7
Units: Participants
ADA positive at baseline (n=7)	0
ADA positive at Cycle 2 Day 1 (n=6)	5
ADA positive at Cycle 7 Day 1 (n=7)	7
ADA positive at Cycle 13 Day 1 (n=5)	5
ADA positive at Cycle 27 Day 1 (n=1)	1
ADA positive at 90 days post last dose (n=4)	4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Part 1: Day 1 through 90 days after the last dose of study drug (approximately 2.8 years); Part 2: Day 1 through 90 days after the last dose of study drug (approximately 2.6 years)

Adverse event reporting additional description

As-treated population included all participants who received any study drugs and were analyzed according to the treatment they actually received.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Part 1 - S1 - FOLFOX + Bevacizumab + Durvalumab + Oleclumab

Reporting group description

Reporting group title

Part 2 - E1 - FOLFOX + Bevacizumab + Durvalumab + Oleclumab

Reporting group description

Reporting group title

Part 2 - C1 - FOLFOX + Bevacizumab

Reporting group description

Serious adverse events	Part 1 - S1 - FOLFOX + Bevacizumab + Durvalumab + Oleclumab	Part 2 - E1 - FOLFOX + Bevacizumab + Durvalumab + Oleclumab	Part 2 - C1 - FOLFOX + Bevacizumab
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 7 (14.29%)	12 / 26 (46.15%)	7 / 26 (26.92%)
number of deaths (all causes)	4	13	8
number of deaths resulting from adverse events	0	3	1
Investigations
Blood bilirubin increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Stoma complication
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Ventricular tachycardia
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Lumbar radiculopathy
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Large intestinal obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	1 / 7 (14.29%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Pyelocaliectasis
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bursitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Rectal abscess
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 7 (0.00%)	2 / 26 (7.69%)	1 / 26 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Sepsis
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Part 1 - S1 - FOLFOX + Bevacizumab + Durvalumab + Oleclumab	Part 2 - E1 - FOLFOX + Bevacizumab + Durvalumab + Oleclumab	Part 2 - C1 - FOLFOX + Bevacizumab
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)	26 / 26 (100.00%)	25 / 26 (96.15%)
Vascular disorders
Hot flush
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	2	0	1
Embolism
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Hypertension
subjects affected / exposed	3 / 7 (42.86%)	4 / 26 (15.38%)	4 / 26 (15.38%)
occurrences all number	5	4	4
Hypotension
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	1 / 26 (3.85%)
occurrences all number	0	1	1
Phlebitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Venous thrombosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
General disorders and administration site conditions
Pain
subjects affected / exposed	0 / 7 (0.00%)	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	0	2	0
Oedema peripheral
subjects affected / exposed	1 / 7 (14.29%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	1	1	0
Mucosal inflammation
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	3 / 26 (11.54%)
occurrences all number	0	3	3
Malaise
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Localised oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Influenza like illness
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Feeling cold
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Fatigue
subjects affected / exposed	5 / 7 (71.43%)	11 / 26 (42.31%)	10 / 26 (38.46%)
occurrences all number	7	12	16
Crepitations
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Chills
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	0	2
Asthenia
subjects affected / exposed	0 / 7 (0.00%)	4 / 26 (15.38%)	2 / 26 (7.69%)
occurrences all number	0	7	3
Temperature intolerance
subjects affected / exposed	1 / 7 (14.29%)	5 / 26 (19.23%)	5 / 26 (19.23%)
occurrences all number	1	5	5
Pyrexia
subjects affected / exposed	2 / 7 (28.57%)	5 / 26 (19.23%)	3 / 26 (11.54%)
occurrences all number	4	11	3
Peripheral swelling
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Respiratory, thoracic and mediastinal disorders
Nasal dryness
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Aphonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Cough
subjects affected / exposed	0 / 7 (0.00%)	3 / 26 (11.54%)	1 / 26 (3.85%)
occurrences all number	0	4	1
Dysphonia
subjects affected / exposed	0 / 7 (0.00%)	2 / 26 (7.69%)	2 / 26 (7.69%)
occurrences all number	0	2	2
Dyspnoea
subjects affected / exposed	1 / 7 (14.29%)	2 / 26 (7.69%)	6 / 26 (23.08%)
occurrences all number	1	3	6
Epistaxis
subjects affected / exposed	0 / 7 (0.00%)	3 / 26 (11.54%)	5 / 26 (19.23%)
occurrences all number	0	4	5
Hiccups
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Laryngospasm
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Pneumonitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Pulmonary embolism
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Rhinorrhoea
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	0	1	2
Throat irritation
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Pulmonary congestion
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Psychiatric disorders
Irritability
subjects affected / exposed	1 / 7 (14.29%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	2	1	0
Insomnia
subjects affected / exposed	1 / 7 (14.29%)	4 / 26 (15.38%)	2 / 26 (7.69%)
occurrences all number	1	4	2
Depression
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	1 / 26 (3.85%)
occurrences all number	0	1	1
Anxiety
subjects affected / exposed	0 / 7 (0.00%)	3 / 26 (11.54%)	1 / 26 (3.85%)
occurrences all number	0	3	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 7 (14.29%)	2 / 26 (7.69%)	4 / 26 (15.38%)
occurrences all number	1	2	4
Aspartate aminotransferase increased
subjects affected / exposed	2 / 7 (28.57%)	2 / 26 (7.69%)	5 / 26 (19.23%)
occurrences all number	3	2	5
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 7 (14.29%)	2 / 26 (7.69%)	3 / 26 (11.54%)
occurrences all number	2	2	3
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Blood creatinine increased
subjects affected / exposed	1 / 7 (14.29%)	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	2	1	2
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	4 / 26 (15.38%)
occurrences all number	0	1	6
International normalised ratio increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Lipase increased
subjects affected / exposed	1 / 7 (14.29%)	4 / 26 (15.38%)	3 / 26 (11.54%)
occurrences all number	1	4	4
Neutrophil count decreased
subjects affected / exposed	4 / 7 (57.14%)	4 / 26 (15.38%)	4 / 26 (15.38%)
occurrences all number	6	5	6
Platelet count decreased
subjects affected / exposed	1 / 7 (14.29%)	3 / 26 (11.54%)	4 / 26 (15.38%)
occurrences all number	1	5	7
Weight decreased
subjects affected / exposed	2 / 7 (28.57%)	2 / 26 (7.69%)	2 / 26 (7.69%)
occurrences all number	2	2	2
Weight increased
subjects affected / exposed	2 / 7 (28.57%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	2	0	0
White blood cell count decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	0	3
Amylase increased
subjects affected / exposed	1 / 7 (14.29%)	2 / 26 (7.69%)	5 / 26 (19.23%)
occurrences all number	1	2	8
Injury, poisoning and procedural complications
Muscle strain
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Contusion
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	1	0	1
Fall
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	1	0	3
Infusion related reaction
subjects affected / exposed	0 / 7 (0.00%)	3 / 26 (11.54%)	3 / 26 (11.54%)
occurrences all number	0	4	5
Wound complication
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Tooth fracture
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Rib fracture
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	4
Atrial fibrillation
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	1 / 26 (3.85%)
occurrences all number	0	1	1
Supraventricular tachycardia
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Palpitations
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Nervous system disorders
Peripheral sensory neuropathy
subjects affected / exposed	5 / 7 (71.43%)	10 / 26 (38.46%)	11 / 26 (42.31%)
occurrences all number	6	10	18
Amnesia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Cognitive disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Dizziness
subjects affected / exposed	1 / 7 (14.29%)	2 / 26 (7.69%)	2 / 26 (7.69%)
occurrences all number	1	2	2
Dysaesthesia
subjects affected / exposed	1 / 7 (14.29%)	1 / 26 (3.85%)	1 / 26 (3.85%)
occurrences all number	1	1	2
Dysgeusia
subjects affected / exposed	2 / 7 (28.57%)	4 / 26 (15.38%)	8 / 26 (30.77%)
occurrences all number	4	4	8
Headache
subjects affected / exposed	1 / 7 (14.29%)	3 / 26 (11.54%)	5 / 26 (19.23%)
occurrences all number	2	3	5
Hypoaesthesia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Memory impairment
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Neuropathy peripheral
subjects affected / exposed	0 / 7 (0.00%)	5 / 26 (19.23%)	3 / 26 (11.54%)
occurrences all number	0	7	3
Neurotoxicity
subjects affected / exposed	0 / 7 (0.00%)	3 / 26 (11.54%)	2 / 26 (7.69%)
occurrences all number	0	6	4
Paraesthesia
subjects affected / exposed	5 / 7 (71.43%)	5 / 26 (19.23%)	7 / 26 (26.92%)
occurrences all number	6	7	7
Peripheral motor neuropathy
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Presyncope
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	1	0	2
Taste disorder
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Tremor
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Syncope
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 7 (14.29%)	2 / 26 (7.69%)	4 / 26 (15.38%)
occurrences all number	1	3	4
Iron deficiency anaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Neutropenia
subjects affected / exposed	0 / 7 (0.00%)	3 / 26 (11.54%)	2 / 26 (7.69%)
occurrences all number	0	5	4
Thrombocytopenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	10
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Vertigo
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Eye disorders
Vision blurred
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	0	2
Visual acuity reduced
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	1 / 26 (3.85%)
occurrences all number	0	1	1
Vitreous floaters
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Gastrointestinal disorders
Haemorrhoids
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Abdominal hernia
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	0	2
Abdominal pain
subjects affected / exposed	1 / 7 (14.29%)	3 / 26 (11.54%)	5 / 26 (19.23%)
occurrences all number	1	4	6
Abdominal pain upper
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	0	3
Ascites
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Constipation
subjects affected / exposed	3 / 7 (42.86%)	12 / 26 (46.15%)	9 / 26 (34.62%)
occurrences all number	4	13	11
Diarrhoea
subjects affected / exposed	5 / 7 (71.43%)	14 / 26 (53.85%)	12 / 26 (46.15%)
occurrences all number	7	19	16
Dry mouth
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	0	2
Dyspepsia
subjects affected / exposed	0 / 7 (0.00%)	2 / 26 (7.69%)	1 / 26 (3.85%)
occurrences all number	0	2	1
Dysphagia
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Flatulence
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 7 (14.29%)	4 / 26 (15.38%)	2 / 26 (7.69%)
occurrences all number	3	4	2
Hypoaesthesia oral
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Nausea
subjects affected / exposed	2 / 7 (28.57%)	12 / 26 (46.15%)	13 / 26 (50.00%)
occurrences all number	2	12	16
Oral dysaesthesia
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Oral pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	1	0	1
Proctalgia
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Rectal haemorrhage
subjects affected / exposed	2 / 7 (28.57%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	2	0	1
Rectal obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	2
Retching
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Stomatitis
subjects affected / exposed	3 / 7 (42.86%)	8 / 26 (30.77%)	5 / 26 (19.23%)
occurrences all number	4	9	5
Vomiting
subjects affected / exposed	0 / 7 (0.00%)	6 / 26 (23.08%)	4 / 26 (15.38%)
occurrences all number	0	13	4
Mouth ulceration
subjects affected / exposed	1 / 7 (14.29%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	1	1	0
Hepatobiliary disorders
Hepatic steatosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Cholelithiasis
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Alopecia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	1 / 26 (3.85%)
occurrences all number	0	1	1
Angioedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Blister
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Cold sweat
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Dermatitis acneiform
subjects affected / exposed	0 / 7 (0.00%)	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	0	2	0
Dry skin
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	0	1	3
Eczema
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Erythema
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Hyperhidrosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Miliaria
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Night sweats
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Onychoclasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	2 / 26 (7.69%)
occurrences all number	0	0	2
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 7 (0.00%)	3 / 26 (11.54%)	0 / 26 (0.00%)
occurrences all number	0	5	0
Photosensitivity reaction
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Rash
subjects affected / exposed	1 / 7 (14.29%)	3 / 26 (11.54%)	0 / 26 (0.00%)
occurrences all number	1	4	0
Rash macular
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Rash maculo-papular
subjects affected / exposed	0 / 7 (0.00%)	2 / 26 (7.69%)	1 / 26 (3.85%)
occurrences all number	0	2	1
Skin discolouration
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Urticaria
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	1	0	1
Dysuria
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	1 / 26 (3.85%)
occurrences all number	0	1	1
Haematuria
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Pollakiuria
subjects affected / exposed	0 / 7 (0.00%)	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	0	2	0
Proteinuria
subjects affected / exposed	2 / 7 (28.57%)	1 / 26 (3.85%)	4 / 26 (15.38%)
occurrences all number	2	1	6
Urinary hesitation
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Urinary incontinence
subjects affected / exposed	0 / 7 (0.00%)	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	0	2	0
Urinary retention
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 7 (14.29%)	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	1	2	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 7 (0.00%)	3 / 26 (11.54%)	2 / 26 (7.69%)
occurrences all number	0	3	3
Arthritis
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Back pain
subjects affected / exposed	1 / 7 (14.29%)	3 / 26 (11.54%)	1 / 26 (3.85%)
occurrences all number	1	3	1
Pain in jaw
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Pain in extremity
subjects affected / exposed	0 / 7 (0.00%)	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	0	3	0
Osteoarthritis
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	2	0	0
Neck pain
subjects affected / exposed	0 / 7 (0.00%)	2 / 26 (7.69%)	1 / 26 (3.85%)
occurrences all number	0	2	1
Myalgia
subjects affected / exposed	1 / 7 (14.29%)	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	1	1	2
Musculoskeletal chest pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Muscular weakness
subjects affected / exposed	1 / 7 (14.29%)	1 / 26 (3.85%)	1 / 26 (3.85%)
occurrences all number	1	1	1
Muscle spasms
subjects affected / exposed	1 / 7 (14.29%)	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	1	1	2
Joint range of motion decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Bone pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Infections and infestations
Eye infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Folliculitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Conjunctivitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Cellulitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Candida infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Bronchitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Anorectal infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	2	0	0
Diarrhoea infectious
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Pharyngitis streptococcal
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Hordeolum
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Gastroenteritis viral
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Fungal skin infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Pneumonia
subjects affected / exposed	1 / 7 (14.29%)	1 / 26 (3.85%)	2 / 26 (7.69%)
occurrences all number	1	1	2
Rash pustular
subjects affected / exposed	0 / 7 (0.00%)	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	0	2	0
Rhinitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Sinusitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Tooth abscess
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
Tooth infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	1	0	1
Upper respiratory tract infection
subjects affected / exposed	1 / 7 (14.29%)	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	1	2	0
Urinary tract infection
subjects affected / exposed	0 / 7 (0.00%)	4 / 26 (15.38%)	1 / 26 (3.85%)
occurrences all number	0	5	1
Vaginal infection
subjects affected / exposed	1 / 7 (14.29%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	1	1	0
Wound infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Medical device site infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	1 / 26 (3.85%)
occurrences all number	0	0	1
COVID-19
subjects affected / exposed	0 / 7 (0.00%)	4 / 26 (15.38%)	0 / 26 (0.00%)
occurrences all number	0	4	0
Metabolism and nutrition disorders
Hyperlipidaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Hyperlipasaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Hyperkalaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Hyperglycaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0
Hyperamylasaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Dehydration
subjects affected / exposed	2 / 7 (28.57%)	5 / 26 (19.23%)	3 / 26 (11.54%)
occurrences all number	4	5	5
Decreased appetite
subjects affected / exposed	1 / 7 (14.29%)	8 / 26 (30.77%)	5 / 26 (19.23%)
occurrences all number	2	9	6
Tumour lysis syndrome
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Increased appetite
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	2	0	0
Hypophosphataemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 26 (0.00%)	3 / 26 (11.54%)
occurrences all number	0	0	3
Hyponatraemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	1 / 26 (3.85%)
occurrences all number	0	1	1
Hypomagnesaemia
subjects affected / exposed	1 / 7 (14.29%)	2 / 26 (7.69%)	0 / 26 (0.00%)
occurrences all number	1	2	0
Hypokalaemia
subjects affected / exposed	0 / 7 (0.00%)	2 / 26 (7.69%)	1 / 26 (3.85%)
occurrences all number	0	3	1
Hypocalcaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Hypoalbuminaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Hyperuricaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Hyperphosphataemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	0	1	0
Hypermagnesaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	1	0	0

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Were there any global substantial amendments to the protocol? Yes

16 May 2019

Section 3.1.3 (Safety Run-in [Part 1]): Revised to further clarify that Part 1 will not involve dose escalation. Section 3.1.5.2 (Safety Review Committee [SRC] [Part 2]): Clarified that the SRC will also be responsible for making recommendations for investigational product dose selection to ensure participants maintain adequate exposure to standard of care treatment. Section 3.1.6 (Management of Study Medication Related Toxicities): Clarified that the toxicity management guidelines provided via the website and Annex to Protocol are applicable to oleclumab. Clarified that guidelines regarding treatment modification and toxicity management for standard of care therapies are provided in Appendix H.

12 Jun 2020

Section (S) 1.6.2.1, 5.3.2: Updated per durvalumab IB edition 15.0. S 1.6.3: Added language to discuss participants with active SARS CoV 2 infection. S 2.2, 2.3: PK, immunogenicity of bevacizumab when used with FOLFOX+novel oncology therapy (Part 2) moved from Secondary Objectives to Exploratory Objectives. S 3.1.2: Specified if leucovorin is not available, use of levoleucovorin at an equivalent dose is acceptable. S 3.1.5, 4.6.1: Clarified that allocation ratio to different arms may be adjusted via protocol amendment after 50 participants are randomized to control arm and the control arm will continue to enroll participants although 50 participants have been enrolled. S 3.1.6.1: Revised language for toxicity management guidelines per sponsor guidelines, added statement to clarify that participants receiving oleclumab + durvalumab should follow durvalumab toxicity management guidelines. S 4.3.2; Table 10, S 4.3.2.2: Clarified requirements for archival and fresh tumor samples. Specified that mandatory biopsies can be waived during SARS-CoV2 pandemic. S 5.3.1: Added this section to indicate that it applies to all biological products used in the study. S 5.3.3: Added section on immune complex disease to align with the potential risks of oleclumab. S 5.5: Updated it to ensure that country-specific regulatory reporting requirements for SAEs are met according to updated sponsor guidelines. Appendix I: Added text to address site and study closure as required in ICH GCP. S 4.1.2: Added statement to inclusion criteria 9, 10 “(except in countries where spermicides are not approved)”. S 4.1.3: Revised Criterion 6 to specify that ECGs will be obtained in triplicate within a 5-minute period at least 1min apart. Revised footnote for ECG in Table 6 to reflect the same. S 4.5.2: Clarified that the use of bevacizumab biosimilars is acceptable in regions/countries where their use is approved. S 4.8.8: Updated to clarify that randomization may be paused during the interim analysis.

11 May 2022

S 2.2: Removed text specifying the PK of bevacizumab will be described only when used in combination with FOLFOX + novel therapy. S 2.2: Clarified that PK for novel agents and bevacizumab are endpoints in Part 1, 2, and Part 1, respectively. S 2.2: Separated statement on immunogenicity objectives into Part 1 and 2, and Part 1. S 2.2: Clarified that the incidence of ADA to novel agents is an endpoint in Part 1 and 2, and ADA to bevacizumab is an endpoint in Part 1. S 2.3: Removed text specifying the PK of bevacizumab/novel agents will be described only when in combination with FOLFOX and clarified that the PK of bevacizumab will be described. Added that immunogenicity of bevacizumab and novel agents will be evaluated in Part 1. Clarified that the immunogenicity of bevacizumab and novel agents will be evaluated in Part 1 and 2, and immunogenicity of bevacizumab will be described in Part 2, and removed text specifying this is only when used in combination with FOLFOX + novel therapy. Separated statement on endpoints into Part 1 and 2, and Part 1. Clarified that an evaluation of ADA will be carried out in Part 1 and 2 as an endpoint. Clarified that the incidence of ADA to bevacizumab in Part 2 is an endpoint. Added table footnote stating that summaries and analyses for exploratory endpoints may be reported outside the CSR in a separate report. S 3.1.7: Clarified that any participants still receiving investigational product (IP) at the time of the data cutoff (DCO) will be able to continue to receive IP. Specified that the DCO refers to the final analysis in the CSR. S 3.2.3: Added endpoints (best overall response, disease control), clarified which endpoints are defined as primary or secondary. S 6.3: Added that participants still receiving IP at the time of “study completion” may be able to continue to receive IP, if, in the investigator’s opinion, the participant is deriving clinical benefit and has not fulfilled any discontinuation criteria.

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.

On 17 February 2022, the decision was made to terminate the clinical study because superior efficacy was not observed for the novel study drug combinations under investigation.

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Clinical trials

Clinical Trial Results: A Phase Ib/II, Open-label, Multicenter Study of Novel Oncology Therapies in Combination with Chemotherapy and Bevacizumab as First-line Therapy in Metastatic Microsatellite-stable Colorectal Cancer (COLUMBIA-1)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part 1

Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part 1

Primary: Number of Participants With Dose Limiting Toxicities (DLTs) in Part 1

Primary: Number of Participants With Dose Limiting Toxicities (DLTs) in Part 1

Primary: Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1

Primary: Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 1

Primary: Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 1

Primary: Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 1

Primary: Percentage of Participants With Objective Response (OR) per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) in Part 2

Primary: Percentage of Participants With Objective Response (OR) per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) in Part 2

Secondary: Percentage of Participants With OR per RECIST v1.1 in Part 1

Secondary: Percentage of Participants With OR per RECIST v1.1 in Part 1

Secondary: Best Overall Response (BOR) per RECIST v1.1 in Part 1

Secondary: Best Overall Response (BOR) per RECIST v1.1 in Part 1

Secondary: Percentage of Participants with Disease Control (DC) per RECIST v1.1 in Part 1

Secondary: Percentage of Participants with Disease Control (DC) per RECIST v1.1 in Part 1

Secondary: Percentage of Participants with PFS at 12 months (PFS-12) per RECIST v1.1 in Part 1

Secondary: Percentage of Participants with PFS at 12 months (PFS-12) per RECIST v1.1 in Part 1

Secondary: Overall Survival (OS) per RECIST v1.1 in Part 1

Secondary: Overall Survival (OS) per RECIST v1.1 in Part 1

Secondary: Progression-Free Survival (PFS) per RECIST v1.1 in Part 1

Secondary: Progression-Free Survival (PFS) per RECIST v1.1 in Part 1

Secondary: Duration of Response (DoR) per RECIST v1.1 in Part 1

Secondary: Duration of Response (DoR) per RECIST v1.1 in Part 1

Secondary: Number of Participants With TEAEs and TESAEs in Part 2

Secondary: Number of Participants With TEAEs and TESAEs in Part 2

Secondary: Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2

Secondary: Number of Participants With at Least 2-Grade Shift From Baseline to Worst Toxicity Grade in Clinical Laboratory Parameters in Part 2

Secondary: Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2

Secondary: Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2

Secondary: BOR per RECIST v1.1 in Part 2

Secondary: BOR per RECIST v1.1 in Part 2

Secondary: PFS per RECIST v1.1 in Part 2

Secondary: PFS per RECIST v1.1 in Part 2

Secondary: Percentage of Participants with DC per RECIST v1.1 in Part 2

Secondary: Percentage of Participants with DC per RECIST v1.1 in Part 2

Secondary: DoR per RECIST v1.1 in Part 2

Secondary: DoR per RECIST v1.1 in Part 2

Secondary: Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1)

Secondary: Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1)

Secondary: OS per RECIST v1.1 in Part 2

Secondary: OS per RECIST v1.1 in Part 2

Secondary: Percentage of Participants with PFS at 12 months (PFS-12) per RECIST v1.1 in Part 2

Secondary: Percentage of Participants with PFS at 12 months (PFS-12) per RECIST v1.1 in Part 2

Secondary: Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1)

Secondary: Serum Concentrations of Oleclumab in Part 1 (S1) and Part 2 (E1)

Secondary: Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1)

Secondary: Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1)

Secondary: Serum Concentrations of Bevacizumab in Part 1 (S1)

Secondary: Serum Concentrations of Bevacizumab in Part 1 (S1)

Secondary: Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1)

Secondary: Number of Participants With Positive ADA to Oleclumab in Part 1 (S1) and Part 2 (E1)

Secondary: Number of Participants With Positive ADA to Bevacizumab in Part 1 (S1)

Secondary: Number of Participants With Positive ADA to Bevacizumab in Part 1 (S1)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase Ib/II, Open-label, Multicenter Study of Novel Oncology Therapies in Combination with Chemotherapy and Bevacizumab as First-line Therapy in Metastatic Microsatellite-stable Colorectal Cancer (COLUMBIA-1)