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
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EudraCT number |
2019-000974-44 |
Trial protocol |
ES |
Global end of trial date |
10 Oct 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Oct 2023
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First version publication date |
22 Oct 2023
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
D910CC00001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04068610 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
AstraZeneca Clinical study Information Center
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Sponsor organisation address |
One MedImmune Way, Gaithersburg, Maryland, United States, 20878
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Public contact |
Global Clinical Lead, AstraZeneca Clinical study Information Center, +1 8772409479, information.center@astrazeneca.com
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Scientific contact |
Global Clinical Lead, AstraZeneca Clinical study Information Center, +1 8772409479, information.center@astrazeneca.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
19 May 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Oct 2022
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Was the trial ended prematurely? |
Yes
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General information about the trial
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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.
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
13 Sep 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 6
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Country: Number of subjects enrolled |
Canada: 3
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Country: Number of subjects enrolled |
France: 4
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Country: Number of subjects enrolled |
Spain: 7
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Country: Number of subjects enrolled |
United States: 39
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Worldwide total number of subjects |
59
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EEA total number of subjects |
11
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
37
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From 65 to 84 years |
22
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at study sites located in Australia, Canada, France, Spain, and United States. | ||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 61 participants were randomized in this study of which 59 participants received treatment. | ||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
MEDI4736
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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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.
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Investigational medicinal product name |
Bevacizumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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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.
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Investigational medicinal product name |
FOLFOX
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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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.
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Investigational medicinal product name |
Oleclumab
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Investigational medicinal product code |
MEDI9447
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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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.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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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.
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Investigational medicinal product name |
FOLFOX
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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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.
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Arm title
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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
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Investigational medicinal product code |
MEDI4736
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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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.
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Investigational medicinal product name |
Bevacizumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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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.
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Investigational medicinal product name |
FOLFOX
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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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.
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Investigational medicinal product name |
Oleclumab
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Investigational medicinal product code |
MEDI9447
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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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.
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Baseline characteristics reporting groups
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Reporting group title |
Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
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Reporting group 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part 2 (C1): FOLFOX + Bevacizumab
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Reporting group 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
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Reporting group 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Part 1 (S1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
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Reporting group 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. | ||
Reporting group title |
Part 2 (C1): FOLFOX + Bevacizumab
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Reporting group 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. | ||
Reporting group title |
Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
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Reporting group 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. |
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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.
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End point type |
Primary
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End point timeframe |
Day 1 through 90 days after the last dose of study drug (approximately 2.8 years)
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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. |
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No statistical analyses for this end point |
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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.
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End point type |
Primary
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End point timeframe |
From Day 1 to 28 days after the first dose of novel oncology therapy (durvalumab and oleclumab)
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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. |
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No statistical analyses for this end point |
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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. |
|||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Part 2 (C1): FOLFOX + Bevacizumab v Part 2 (E1): FOLFOX + Bevacizumab + Durvalumab + Oleclumab
|
||||||||||||
Number of subjects included in analysis |
52
|
||||||||||||
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 |
|
|||||||||||||||||
End point title |
Best Overall Response (BOR) per RECIST v1.1 in Part 1 [10] | ||||||||||||||||
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 [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. |
|||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Percentage of Participants With OR per RECIST v1.1 in Part 1 [11] | ||||||||
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 [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. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Percentage of Participants with PFS at 12 months (PFS-12) per RECIST v1.1 in Part 1 [12] | ||||||||
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 [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. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Progression-Free Survival (PFS) 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 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 [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. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
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. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Duration of Response (DoR) per RECIST v1.1 in Part 1 [15] | ||||||||
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 [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. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Percentage of Participants with Disease Control (DC) per RECIST v1.1 in Part 1 [16] | ||||||||
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 [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. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 [17] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 [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. |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of Participants With TEAEs and TESAEs in Part 2 [18] | |||||||||||||||
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 [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. |
||||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Number of Participants With Abnormal Vital Signs Reported as TEAEs in Part 2 [19] | |||||||||||||||||||||||||||
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 |
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. |
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
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. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
OS per RECIST v1.1 in Part 2 [24] | ||||||||||||
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 [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. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Percentage of Participants with PFS at 12 months (PFS-12) per RECIST v1.1 in Part 2 [25] | ||||||||||||
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 [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. |
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|
|||||||||||||
No statistical analyses for this end point |
|
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End point title |
Serum Concentrations of Durvalumab in Part 1 (S1) and Part 2 (E1) [26] | |||||||||||||||||||||||||||
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.
|
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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 [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. |
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|
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No statistical analyses for this end point |
|
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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.
|
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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. |
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|
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No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Serum Concentrations of Bevacizumab in Part 1 (S1) [28] | ||||||||||||||||||
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 [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. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Number of Participants With Positive Anti-Drug Antibodies (ADA) to Durvalumab in Part 1 (S1) and Part 2 (E1) [29] | |||||||||||||||||||||||||||
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 [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. |
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|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
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.
|
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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. |
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|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
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. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
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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)
|
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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.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
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Reporting groups
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Reporting group title |
Part 1 - S1 - FOLFOX + Bevacizumab + Durvalumab + Oleclumab
|
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part 2 - E1 - FOLFOX + Bevacizumab + Durvalumab + Oleclumab
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Part 2 - C1 - FOLFOX + Bevacizumab
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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. |
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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. |
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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. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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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. |