Experimental arm only: Cycles 4, 10, 16, 22, 30, 38, 46, 58 and every 12 cycles thereafter
Experimental Arm only
▼ Matches across tablesall 1 decided
Rows that consolidation merged on name similarity, or kept separate from a near match. Whether two rows are the same activity is the reviewer's call: choosing drafts an entry for NCT02291289_consolidation_corrections.json below; nothing is saved from here. Rows merged on an identical name are not listed. Words that only one of the two names prints are marked; the score ignores case, hyphens, slashes, text in parentheses and plural endings.
A second, cohort-specific consent. Kerstin Forsberg, 2026-10-04T08:20:00Z
Draft — entries to append to consolidated/NCT02291289_consolidation_corrections.json; replace each <why>, then re-run consolidation.
▼ Consolidation MetadataProcess information
consolidated_at
2026-10-04T08:21:17.319832+00:00
source_activity_count
118
unified_activity_count
36
compression_percent
69
match_stats
exact: 82, new: 36
▼ Source Tables5 tables
table
type
track
title / purpose
acts
cols
props
T1
main_soa
Appendix 1 Schedule of Assessments for All Patients (Screening / Baseline and Induction Treatment Phase) Screening/Baseline and Induction Treatment Phase schedule for all patients, with Study Treatment Discontinuation Visit and Post-Treatment Follow-up for patients not entering maintenance
21
6
3
T2
track
Cohort 1
Appendix 2 Schedule of Assessments during Maintenance Phase (Cohort 1) Maintenance Treatment Phase schedule for patients assigned to Cohort 1
25
4
2
T3
track
Cohort 2
Appendix 3 Schedule of Assessments during Maintenance Phase (Cohort 2) Maintenance Treatment Phase schedule for patients assigned to Cohort 2
24
4
2
T4
track
Cohort 3
Appendix 4 Schedule of Assessments during Maintenance Phase (Cohort 3) Maintenance Treatment Phase schedule for patients assigned to Cohort 3
22
4
2
T5
track
Cohort 4
Appendix 5 Schedule of Assessments during Maintenance Phase (Cohort 4) Maintenance Treatment Phase schedule for patients assigned to Cohort 4
26
4
2
▼ Unified Activities36 activities
xact_id
activity_name (variations)
parent
match
#
tables
row kind
xact-001
Informed consent
one table
1
T1
xact-002
Confirmation of general eligibility
one table
1
T1
xact-003
Demographics and medical history
one table
1
T1
xact-004
Vital signs and weight
same name
5
T1, T2, T3, T4, T5
xact-005
Physical examination
same name
5
T1, T2, T3, T4, T5
xact-006
ECOG performance status
same name
5
T1, T2, T3, T4, T5
xact-007
Concomitant medications
same name
5
T1, T2, T3, T4, T5
xact-008
Haematology and blood chemistry
same name
5
T1, T2, T3, T4, T5
xact-009
INR, aPTT (select patients)
same name
5
T1, T2, T3, T4, T5
xact-010
Urinalysis (dipstick)
same name
5
T1, T2, T3, T4, T5
xact-011
Pregnancy test
same name
5
T1, T2, T3, T4, T5
xact-012
Tumour assessments
same name
5
T1, T2, T3, T4, T5
xact-013
Archival primary tumour tissue for biomarker assessment
one table
1
T1
xact-014
Metastatic tumour tissue for exploratory biomarker assessment
same name
5
T1, T2, T3, T4, T5
xact-015
Whole blood sample
one table
1
T1
xact-016
Plasma samples
same name
5
T1, T2, T3, T4, T5
xact-017
Stool sample
same name
5
T1, T2, T3, T4, T5
xact-018
Adverse events (including SAEs)
same name
5
T1, T2, T3, T4, T5
xact-019
Study medication administration
same name
5
T1, T2, T3, T4, T5
xact-020
Subsequent anti-cancer therapies
same name
5
T1, T2, T3, T4, T5
xact-021
Patient survival
same name
5
T1, T2, T3, T4, T5
xact-022
Assignment of cohort
same name
4
T2, T3, T4, T5
xact-023
Cohort-specific informed consent
same name
4
T2, T3, T4, T5
xact-024
Confirmation of cohort-specific eligibility
same name
4
T2, T3, T4, T5
xact-025
Randomisation
same name
4
T2, T3, T4, T5
xact-026
Head and neck assessment for SCC
one table
1
T2
xact-027
Chest CT assessment for SCC
one table
1
T2
xact-028
Dermatology evaluation
one table
1
T2
xact-029
Anal and pelvic exam
one table
1
T2
xact-030
12-lead ECG
one table
1
T2
xact-031
TSH, free or total T3, free or total T4
same name
2
T3, T5
xact-032
Pulse oximetry
same name
2
T3, T5
xact-033
Tuberculosis test
same name
2
T3, T5
xact-034
HIV, HBV, HCV serology
same name
3
T3, T4, T5
xact-035
LVEF
same name
2
T4, T5
xact-036
Ophthalmology exam
one table
1
T5
▼ Unified Annotations81 annotations (33% dedup from 121)
Footnote (79)
xannot_id
markers
#
text
scope
points to
xannot-001 1
T1:a
1
With the exception of Cycle 1, all other study visits and assessments should be performed within ± 7 days of the scheduled date.
Patients who experience PD during or at the end of the Induction Treatment Phase, or who refuse to go into the Maintenance Treatment Phase or who are not eligible for any study cohort, will undergo a Study Treatment Discontinuation Visit within 30 days after the last dose of study medication. These patients will then enter the Post-Treatment Follow-up Phase. All patients need to be evaluated for potential resection of metastasis at completion of the induction period. This is of particular importance for patients with liver metastases. If the patient is found to be resectable they will undergo a Study Treatment Discontinuation Visit within 30 days after the last dose of study treatment and will then enter the Post-Treatment Follow-up Phase.
Study Treatment Discontinuation Visit
xannot-003 3
T1:c
1
Patients in the Post-Treatment Follow-up Phase will be followed up every 3 months after their Study Treatment Discontinuation Visit. During post-treatment follow-up subsequent anti-cancer therapies will be recorded and survival assessed up to May 31, 2019 only. Refer to Appendix 19 for management of patients based on their study status on May 31, 2019. Treatment during the Post-Treatment Follow-up Phase is at the Investigator’s discretion; BRAFmut/MSS patients experiencing early disease progression during induction treatment will have the option of proceeding immediately to receive second-line treatment with 5-FU/LV, cetuximab and vemurafenib; BRAFmut/MSI-H patients experiencing early disease progression during induction treatment will have the option of proceeding immediately to receive second-line treatment with a fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab and atezolizumab. See Section 3.1.1.1 for further details including if disease progression occurs prior to availability of study biomarker test results in a patient with a previous BRAF mutation-positive result (e.g. by local test). Patients who discontinue study treatment during the Induction Treatment Phase prior to disease progression will also continue to be followed for PFS, with disease status followed according to local practice until progression or May 31, 2019, whichever comes first. Disease status will not be collected for the study after May 31, 2019.
Written informed consent for participation in the study must be obtained before performing any study-specific screening tests or evaluations and before shipping primary tumour blocks or slides to the Sponsor-designated laboratory. However, results from routine assessments conducted prior to informed consent signature may be used as screening assessments as long as they were done within 7 days prior to informed consent signature.
Informed consent
xannot-005 5
T1:e
1
The “All Cohort” eligibility criteria are evaluated prior to initiating the first cycle of study treatment during the Induction Treatment Phase.
Confirmation of general eligibility
xannot-006 6
T1:f
1
Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive status, smoking history, use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by the patient within 7 days prior to the Screening visit. Demographic data will include age, sex, and self-reported race/ethnicity (where permitted by federal regulations).
Demographics and medical history
xannot-007 7
T1:g
1
Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature. During Screening, weight only required ≤ 7 days.
Vital signs and weight
xannot-008 8
T1:h
1
Baseline assessment requires a complete physical exam. A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems. Abnormalities identified at Screening / Baseline will be recorded as baseline conditions. At subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations should be performed. Changes from Baseline, with new or worsened clinically significant abnormalities, should be reported as AEs if appropriate.
Physical examination
xannot-009 9
T1:i
1
ECOG status assessed within 7 days prior to Day 1 of Cycle 1 (Induction Treatment Phase) for eligibility determination. See Appendix 8.
ECOG performance status
Appendix 8
xannot-010 10
T1:j
1
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to the date of informed consent up until the date of study discontinuation. Only concomitant medications used for supportive care, to alleviate symptoms of mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent visits, only changes to current medications or medications used since the last documentation of medications will be recorded. Concomitant medications for treatment of AEs related to study medication will continue to be recorded while the AE is being followed. For permitted and prohibited concomitant medications, see Section 4.4.
Concomitant medications
Section 4.4
xannot-011 11
T1,3:k
2
Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry includes ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, phosphorus, sodium, potassium, chloride, and bicarbonate. Hematology and blood chemistry tests must be conducted prior to each treatment cycle, with the results available for review prior to start of treatment according to local standards for treatment management. However, only tests conducted every second treatment cycle will be recorded in the eCRF. Clinical laboratory results constituting a clinically significant AE should be recorded as such.
Haematology and blood chemistry
xannot-012 12
T1:l
1
INR and aPTT are required for all patients at screening but only for patients receiving anticoagulants while on protocol-specified treatment.
INR, aPTT (select patients)
xannot-013 13
T1:m
1
Urinalysis must be performed by dipstick at Baseline and within 48 hours prior to every cycle. A 24-hour urine collection is needed in the event of proteinuria ≥ ± 2 by dipstick test.
Urinalysis (dipstick)
xannot-014 14
T1:n
1
Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-induced amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation. A serum pregnancy test is required within 7 days prior to start of study induction treatment, or within 14 days with a confirmatory urine pregnancy test within 7 days prior start of study induction treatment
Pregnancy test
xannot-015 15
T1:o
1
Will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. Include upper abdomen at Baseline. A CT or MRI scan of the brain is required if there is clinical suspicion of CNS metastases at screening/Baseline or at any time during the Induction Treatment Phase. Subsequent tumour assessments will be done according to standard of care at each study centre, with the exception that all patients must have a tumour assessment at the end of the Induction Treatment Phase. Tumour assessments are not required for study purposes after disease progression has been documented. Patients who discontinue study treatment during the Induction Treatment Phase prior to disease progression will also continue to be followed for progressive disease, with disease status followed according to local practice until progression or May 31, 2019, whichever comes first. After May 31, 2019, disease status will not be collected for the study.
Tumour assessments
xannot-016 16
T1:p
1
Archival tumour tissue (FFPET) block from the primary tumour obtained at the time of the initial diagnosis. If the tumour block is not available, ≥ 20 slides cut from the primary tumour sample will be accepted as an alternative. Before a patient can be enrolled, the sample (block or slides) must be shipped to the designated laboratory with the corresponding pathology report and receipt of the shipment must be confirmed by the laboratory. See Appendix 17.
Archival primary tumour tissue for biomarker assessment
Appendix 17
xannot-017 17
T1:q
1
Collection of the optional core biopsy of metastatic tumours was discontinued as of May 2018. (See Appendix 18).
Metastatic tumour tissue for exploratory biomarker assessment
Appendix 18
xannot-018 18
T1:r
1
Whole blood and plasma samples will be collected from all study patients for exploratory biomarker analyses unless genomic analysis is not allowed per local regulations. In such instances, only plasma samples will be collected. All samples will be sent to a designated laboratory. Samples during treatment should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified (see Appendix 17 and Laboratory Manual).
Whole blood sample | Plasma samples
Appendix 17
xannot-019 19
T1:s
1
After the signing of the informed consent form, and prior to Day 1 of Cycle 1 (Induction Treatment Phase), any SAEs thought to be related to a protocol-mandated intervention should be reported. Adverse events will be documented at every cycle during treatment. All patients will be followed for new AEs for 28 days following the discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed until the event resolves, the Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws consent. Death related to disease progression is not considered to be an SAE. The Sponsor should be notified if the Investigator becomes aware of any SAE or AEs of special interest occurring after the end of the adverse event reporting period if the event is believed to be related to prior study treatment.
Adverse events (including SAEs)
xannot-020 20
T1:t
1
Eligible patients will enter a 4-month Induction Treatment Phase. Treatment during this phase, based on Investigator’s choice, will be either eight 2-week cycles of 5-FU, LV and oxaliplatin (FOLFOX) in combination with bevacizumab or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
Study medication administration
xannot-021 21
T1:n1
1
Collection of these samples discontinued as of May 2018
Metastatic tumour tissue for exploratory biomarker assessment
xannot-022 22
T1:n2, T2-5:n1
5
Supplemental Biomarker Program closed as of May 2018. Collection of these samples has been discontinued.
Stool sample | Metastatic tumour tissue for exploratory biomarker assessment
xannot-024 24
T2,5:a
2
With the exception of Cycle 1, all other study visits and assessments should be performed within ± 7 days of the scheduled date. If a control arm patient receives capecitabine administered according to a 3- week cycle, timing of all study procedures and assessments scheduled according to 2-week treatment cycles (e.g. ECOG performance status) will be defined by the treatment cycles of concurrently administered bevacizumab.
Patients who experience PD at any time during the Maintenance Treatment Phase, or who need to permanently discontinue study medication for any reason, will undergo a Study Treatment Discontinuation Visit within 30 days after the last dose of study medication. These patients will then enter the Post-Treatment Follow-up.
Study Treatment Discontinuation Visit | Study Treatment Discontinuation Visit | Study Treatment Discontinuation Visit | Study Treatment Discontinuation Visit
xannot-026 26
T2:c
1
After discontinuation of study treatment and the Study Discontinuation Visit, patients will enter the Post-Treatment Follow-up Phase. Beginning after the Study Treatment Discontinuation visit, patients will be followed up every 3 months. Up to and including May 31, 2019, follow-up will include disease status (patients discontinuing study treatment prior to disease progression only) in addition to safety evaluations and recording of subsequent anti-cancer therapies and survival. After May 31, 2019, disease status will not be documented for study purposes. Treatment during the Post-Treatment Follow-up Phase is at the Investigator’s discretion. Patients who discontinue study treatment prior to disease progression will be followed for PFS, with disease status followed every 8 weeks until progression or May 31, 2019, whichever comes first.
Patients completing the Induction Treatment Phase, and who have not experienced PD can then proceed to the Maintenance Treatment Phase. Depending on the patient’s biomarker status (based on the archival sample from initial diagnosis), these patients will be assigned to a maintenance treatment cohort. Cohorts 2 and 4 are closed to further enrolment. Patients with an adequate tumour sample but with unknown biomarker status due to lack of determinant result (e.g. due to technical issues) may still be included in the study depending on the addition of future cohorts.
Assignment of cohort
xannot-028 28
T2-5:e
4
The cohort-specific exclusion criteria must be assessed prior to randomization to study maintenance treatment but assessment of cohort-specific eligibility can only be completed after the biomarker analysis results from the patient’s archival tumour tissue from initial diagnosis are known. Patients found ineligible for any cohort will undergo a Study Treatment Discontinuation Visit and enter the Post-Treatment Follow-up Phase.
Confirmation of cohort-specific eligibility
xannot-029 29
T2-5:f
4
Each cohort will consist of an experimental treatment arm and a control arm. Randomised on a 2:1 (experimental:control) basis to either the experimental treatment arm or the control arm of that cohort. See Section 4.2.
Randomisation
Section 4.2
xannot-030 30
T2:g
1
Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature.
Vital signs and weight
xannot-031 31
T2-5:h
4
Physical examinations will be symptom-directed, and will include changes from Baseline (pre-Induction) with new or worsened clinically significant abnormalities being reported as AEs if appropriate.
Physical examination
xannot-032 32
T2:i
1
To be performed by the Investigator or other qualified physician as part of the evaluation for SCC. The head and neck examination will consist of at least a visual inspection of the oral mucosa and lymph node palpation. Any suspicious findings will be referred to an appropriate specialist.
Head and neck assessment for SCC
xannot-033 33
T2:j
1
The routinely scheduled radiographic assessment for tumour burden may be used (if available) as the chest CT for the evaluation of non-cutaneous SCC. MRI may be used if a CT scan is contra-indicated for the patient.
Chest CT assessment for SCC
xannot-034 34
T2:k
1
Evaluation to be performed by a dermatologist, the Investigator or other qualified physician.
Dermatology evaluation
xannot-035 35
T2:l
1
Pelvic examinations for women (with special attention to cervix) and anal examinations for all patients will be performed by the Investigator or other qualified physician prior to start of Experimental Therapy and at the Study Treatment Discontinuation Visit for the evaluation of SCC. The pelvic examination should include a complete external and internal examination (internal examination of uterine cervix may include a Pap smear, which would be a decision of the Investigator). The anal examination should include external examination, digital anorectal examination and anoscopy or proctoscopy. However, if in opinion of the Investigator the presence of “abnormal lesions including SCC” can be excluded by the external inspection and the manual examination, this is acceptable. However, if the presence of a lesion is suspected, an anoscopy or proctoscopy are recommended.
Anal and pelvic exam
xannot-037 37
T2:n
1
ECG to determine Cohort 1 eligibility must conducted within 3 weeks of randomization. During maintenance treatment, ECGs will be required in experimental arm patients only. Measurements include heart rate, PR interval, QRS duration, and QT and QTc intervals.
12-lead ECG
xannot-038 38
T2:o, T3-5:j
4
Concomitant medication includes any prescription medications or over-the-counter preparations used by a patient between the 7 days prior to the date of informed consent up until the Study Treatment Discontinuation visit. Only concomitant medications used for supportive care, to alleviate symptoms of mCRC, or to treat adverse drug reactions should be recorded on the Concomitant Medications eCRF. At subsequent visits, only changes to current medications or medications used since the last documentation of medications will be recorded. Concomitant medications for treatment of AEs related to study medication will continue to be recorded while the AE is being followed. For permitted and prohibited concomitant medications, see Section 4.4.
Concomitant medications
Section 4.4
xannot-039 39
T2:p
1
Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry includes ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, phosphorus, sodium, potassium, chloride and bicarbonate. Patients in the experimental arm will also have magnesium, amylase and lipase tested. Haematology and blood chemistry tests must be conducted prior to each treatment cycle, with the results available for review prior to start of treatment according to local standards for treatment management. However, only tests conducted every second treatment cycle will be recorded in the eCRF. Clinical laboratory results constituting a clinically significant AE should be recorded as such.
Haematology and blood chemistry
xannot-040 40
T2:q, T3-5:l
4
INR and aPTT only for patients receiving anticoagulants while on protocol-specified treatment.
INR, aPTT (select patients)
xannot-041 41
T2:r
1
Urinalysis must be performed by dipstick within 48 hours prior to every cycle. A 24-hour urine collection is needed in the event of proteinuria ≥ ± 2 by dipstick test. Urinalysis results from every second cycle only will be recorded in the CRF.
Urinalysis (dipstick)
xannot-042 42
T2:s, T3,5:n
3
Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-induced amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation. If urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
Pregnancy test
xannot-043 43
T2:t
1
Up to and including May 31, 2019, tumour assessments will be conducted according to RECIST 1.1 for Cohort 1 with disease status during maintenance treatment determined based on comparison with the tumour assessment done at the end of induction treatment. Assessments will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. A CT or MRI scan of the brain is required if there is a clinical suspicion of CNS metastases. Up to and including May 31, 2019, tumour assessments will be conducted every eight weeks from the start of maintenance treatment regardless of treatment delays. After May 31, 2019, disease status will not be collected for the study and tumour assessments may be conducted per local practice. Patients who discontinue study treatment during the Maintenance Treatment Phase prior to disease progression will also continue to be followed for progressive disease, with disease assessments per RECIST 1.1 conducted every eight weeks until progression or May 31, 2019, whichever comes first.
Tumour assessments
xannot-044 44
T2:u, T3-4:r, T5:t
4
Supplemental Biomarker Program closed as of May 2018. Collection of these samples has been discontinued (see Appendix 18).
Metastatic tumour tissue for exploratory biomarker assessment
Appendix 18
xannot-045 45
T2:v, T3-4:s
3
Plasma samples will be collected from all patients for exploratory biomarker analyses. These samples will be sent to a designated laboratory. Samples during treatment should be taken within 48 hours prior to study treatment Day 1 of each cycle indicated, unless otherwise specified (see Appendix 17 and the Laboratory Manual).
Plasma samples
Appendix 17
xannot-046 46
T2:w
1
Adverse events will be documented at every cycle during treatment. All patients will be followed for new AEs for 28 days following the discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed until the event resolves, the Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws consent. Death related to disease progression is not considered to be an SAE. The Sponsor should be notified if the Investigator becomes aware of any SAE or AEs of special interest occurring after the end of the adverse event reporting period if the event is believed to be related to prior study treatment.
Adverse events (including SAEs)
xannot-047 47
T2:x
1
Patients in the Experimental Arm will receive: The first six patients in this cohort received 1,600 mg/m2 5-FU administered via 46-hour IV infusion, in combination with LV 400 mg/m2 administered via 2-hour infusion, on Day 1 of every 2-week cycle. Based on results of February 2016 iDMC recommendations, subsequent patients in this cohort will receive 1,600 - 2,400 mg/m2 5-FU administered via 46-hour IV infusion (IV bolus is not permitted), in combination with LV 400 mg/m2 administered via 2-hour infusion, on Day 1 of every 2-week cycle. In addition, patients will receive cetuximab 500 mg/m2 via IV infusion on Day 1 of every 2-week cycle and vemurafenib 960 mg b.i.d. orally. Patients in the Control arm will receive: 5-FU or capecitabine, dose and schedule will be according to local label, where applicable, or otherwise will be determined per the Investigator’s discretion, with bevacizumab 5 mg/kg via 15 – 30 minute IV infusion on Day 1 of every 2-week cycle. If a control arm patient receives capecitabine administered according to a 3- week cycle, timing of all study procedures and assessments scheduled according to 2-week treatment cycles (e.g. ECOG performance status) will be defined by the treatment cycles of concurrently administered bevacizumab.
Study medication administration
xannot-048 48
T2,3,5:n2
3
Experimental Arm only
Head and neck assessment for SCC | Chest CT assessment for SCC | Dermatology evaluation (+3)
xannot-049 49
T3:a
1
With the exception of Cycle 1, all other study visits and assessments should be performed within ± 7 days of the scheduled date. If a patient receives capecitabine administered according to a 3-week cycle, timing of all study procedures and assessments scheduled according to 2-week treatment cycles (e.g. ECOG performance status) will be defined by the treatment cycles of concurrently administered bevacizumab (control arm) or the treatment cycles of concurrently administered bevacizumab and atezolizumab (experimental arm).
Maintenance Treatment Phase
xannot-050 50
T3:c
1
After discontinuation of study treatment and the Study Treatment Discontinuation Visit, patients will enter the Post-Treatment Follow-up Phase. Beginning after the Study Treatment Discontinuation Visit, patients will be followed up every 3 months. Up to and including May 31, 2019, follow-up will include recording subsequent anti-cancer therapies, disease status (until progression as applicable), survival and safety evaluations. Patients who have completed the adverse event reporting period will be discontinued from the study at the post-treatment follow-up visit within the 3 months prior to and including May 31, 2019 (i.e. at the visit on/after March 1, 2019). After May 31, 2019, patients who have not yet completed the adverse event reporting period will be discontinued from the study after completion of the adverse event reporting period. Refer to Appendix 19 for the management of patients based on their study status as of May 31, 2019. Treatment during the Post-Treatment Follow-up Phase is at the Investigator’s discretion, however, patients treated with atezolizumab should not receive other immunomodulatory agents for 10 weeks after study treatment discontinuation. Patients who discontinue study treatment prior to disease progression will be followed for PFS, with disease status followed every 8 weeks until progression or May 31, 2019, whichever comes first.
Patients completing the Induction Treatment Phase, and who have not experienced PD can then proceed to the Maintenance Treatment Phase. Depending on the patient’s biomarker status (based on the archival sample from initial diagnosis), these patients will be assigned to a maintenance treatment cohort. Cohorts 2 and 4 are closed to further accrual. Patients with an adequate tumour sample but with unknown biomarker status due to lack of determinant result (e.g. due to technical issues) may still be included in the study depending on the addition of future cohorts.
Assignment of cohort
xannot-052 52
T3:g
1
Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature. Experimental arm only: For the first atezolizumab infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressures, and temperature) should be determined within 60 minutes before the infusion, every 15 ± 5 minutes during the infusion, and 30 ± 10 minutes after the infusion. For subsequent infusions, vital signs will be collected within 60 minutes before the infusion and should be collected during or after the infusion if clinically indicated or if symptoms occurred in the prior infusion. Vital sign measurements from every second treatment cycle only will be recorded in the CRF.
Vital signs and weight
xannot-053 53
T3:m
1
Urinalysis must be performed by dipstick within 48 hours prior to every cycle. A 24-hour urine collection is needed in the event of proteinuria ≥ ± 2 by dipstick test. Results from every second cycle only will be recorded in the CRF.
Urinalysis (dipstick)
xannot-054 54
T3:o
1
Patients with active tuberculosis are not eligible for Cohort 2 and will be excluded from entering the Maintenance Phase of the study. Investigators must confirm absence of active disease in patients with a positive test.
Tuberculosis test
xannot-055 55
T3:p
1
HIV testing performed in accordance with national and/or institutional guidelines. HBV serology includes HBsAg and anti-HBc. HCV serology includes anti-HCV. Results required to determine eligibility for Cohort 2.
HIV, HBV, HCV serology
xannot-056 56
T3:q
1
Up to and including May 31, 2019, tumour assessments will be conducted according to RECIST1.1 for Cohort 2, and additionally according to mRECIST for the experimental arm of Cohort 2. Assessments will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. A CT or MRI scan of the brain is required if there is a clinical suspicion of CNS metastases. Disease status during maintenance treatment will be determined based on comparison with the tumour assessment done at the end of induction treatment. Up to and including May 31, 2019, tumour assessments will be conducted every 8 weeks from the start of maintenance treatment regardless of treatment cycle delays. After May 31, 2019, disease status will not be collected for the study and tumour assessments may be conducting per local practice. Tumour assessments for Cohort 2 control arm patients will not be collected for study purposes after disease progression per RECIST 1.1 has been documented or May 31, 2019, whichever occurs first. Tumour assessments for Cohort 2 experimental arm patients will not be collected for study purposes after disease progression per mRECIST has been documented or May 31, 2019, whichever occurs first. Patients who discontinue study treatment during the Maintenance Treatment Phase prior to disease progression will also continue to be followed for progressive disease, with disease assessments per RECIST 1.1 or mRECIST (as described above) conducted every 8 weeks until progression or May 31, 2019, whichever comes first.
Tumour assessments
xannot-057 57
T3:t
1
Adverse events will be documented at every cycle during treatment. Patients in the experimental arm of Cohort 2 will be followed for new AEs for 90 days following the discontinuation of study treatment. Patients in the control arm will be followed for new AEs for 28 days following the discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed until the event resolves, the Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws consent. Death related to disease progression is not considered to be an SAE. The Sponsor should be notified if the Investigator becomes aware of any SAE or AEs of special interest occurring after the end of the adverse event reporting period if the event is believed to be related to prior study treatment.
Adverse events (including SAEs)
xannot-058 58
T3:u
1
Patients in the Experimental Arm will receive 5-FU or capecitabine 1,600 – 2,400 mg/m2 5-FU administered via 46-hour IV infusion (IV bolus is not permitted) and LV 400 mg/m2 administered via a 2-hour infusion given day 1 every 2 weeks; or 1000 mg/m2 b.i.d. capecitabine given days 1-14 every 2 weeks followed by a one-week treatment break. Atezolizumab at a fixed dose of 800 mg administered via 60-minute IV infusion on Day 1 of every 2-week cycle (if initial infusion is well tolerated, subsequent infusions will be done over a 30-minute time period) and bevacizumab 5 mg/kg via 15 – 30 minute IV infusion on Day 1 of every 2-week cycle. Patients in the Control arm will receive: 5-FU or capecitabine, dose and schedule will be according to local label, where applicable, or otherwise will be determined per the Investigator’s discretion, with bevacizumab 5 mg/kg via 15 – 30 minute IV infusion on Day 1 of every 2-week cycle. If a patient receives capecitabine administered according to a 3-week cycle, timing of all study procedures and assessments scheduled according to 2-week treatment cycles (e.g. ECOG performance status) will be defined by the treatment cycles of concurrently administered bevacizumab (control arm) or concurrently administered bevacizumab and atezolizumab (experimental arm).
Study medication administration
xannot-059 59
T4:a
1
With the exception of Cycle 1, all other study visits and assessments should be performed within ± 7 days of the scheduled date. If a control arm patient receives capecitabine administered according to a 3- week cycle, timing of all study procedures and assessments scheduled according to 2-week control arm treatment cycles (e.g. ECOG performance status) will be defined by the treatment cycles of concurrently administered bevacizumab.
Maintenance Treatment Phase
xannot-060 60
T4:c
1
After discontinuation of study treatment and the Study Treatment Discontinuation Visit, patients will enter the Post-Treatment Follow-up Phase. Beginning after the Study Treatment Discontinuation Visit, patients will be followed up every 3 months. Up to and including May 31, 2019, follow-up will include recording subsequent anti-cancer therapies, disease status (until progression as applicable), survival and safety evaluations. Patients who have completed the adverse event reporting period and, if applicable, 7 month post-treatment pregnancy test will be discontinued from the study at the post-treatment follow-up visit within the 3 months prior to and including May 31, 2019 (i.e. at the visit on/after March 1, 2019). After May 31, 2019, patients who have not yet completed the adverse event reporting period (and 7 month pregnancy test as applicable) will be discontinued from the study after completion of the adverse event reporting period (and 7 month pregnancy test as applicable). Refer to Appendix 19 for the management of patients based on their study status as of May 31, 2019. Treatment during the Post-Treatment Follow-up Phase is at the Investigator’s discretion. Patients who discontinue study treatment prior to disease progression will be followed for PFS, with disease status followed every 8 weeks until progression or May 31, 2019, whichever comes first.
Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature. For the control arm only, vitals conducted every second treatment cycle only will be recorded in the eCRF.
Vital signs and weight
xannot-062 62
T4:k
1
Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry includes ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, phosphorus, sodium, potassium, chloride, and bicarbonate. Haematology and blood chemistry tests must be conducted prior to each treatment cycle, with the results available for review prior to start of treatment according to local standards for treatment management. For the control arm only, tests conducted every second treatment cycle only will be recorded in the eCRF. Clinical laboratory results constituting a clinically significant AE should be recorded as such.
Haematology and blood chemistry
xannot-063 63
T4:m
1
Urinalysis must be performed by dipstick within 48 hours prior to every cycle. A 24-hour urine collection is needed in the event of proteinuria ≥ ± 2 by dipstick test. For the control arm only, tests conducted every second treatment cycle only will be recorded in the eCRF.
Urinalysis (dipstick)
xannot-064 64
T4:n
1
Urine or blood pregnancy test, only for women of childbearing potential (i.e. not post-menopausal as indicated by < 12 months of non-therapy-induced amenorrhea, nor surgically sterile [absence of ovaries and/or uterus]), including those who have had a tubal ligation. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. In the experimental arm, a serum pregnancy test must be done ≤ 7 days from maintenance treatment start. Urine pregnancy tests must also be done every 3 cycles during treatment (with result available prior to Day 1 dose of the next cycle), and every 3 months until 7 months after the last doses of trastuzumab and pertuzumab.
Pregnancy test
xannot-065 65
T4:o
1
HIV testing performed in accordance with national and/or institutional guidelines. HBV serology includes HBsAg and anti-HBc. HCV serology includes anti-HCV. Results required to determine eligibility for Cohort 3.
HIV, HBV, HCV serology
xannot-066 66
T4:p
1
LVEF must be assessed in all Cohort 3 patients prior to randomization. Only experimental arm patients require subsequent LVEF monitoring. Subsequent LVEF measurements (using the same method as at baseline) will be conducted every third cycle until Cycle 6 and then every fourth cycle until termination of study treatment (i.e., during Cycles 3, 6, 10, 14, etc.), with the results made available prior to administration of the subsequent treatment cycle (i.e., prior to Cycles 4, 7, 11, 15, etc.). For patients who stop study drug(s) because of a decrease in LVEF, LVEF should be assessed at least every 6 weeks to determine recovery/stabilization (until LVEF recovers to ≥ 50% or 2 years, whichever occurs first). In patients who required a repeat LVEF assessment to ensure an acceptable LVEF before continuing trastuzumab/pertuzumab treatment, an additional LVEF assessment is to be performed at the next treatment cycle. Note: approval of the Medical Monitor must be obtained before continuation of study treatment after delays > 21 days.
LVEF
xannot-067 67
T4:q
1
Up to and including May 31, 2019, tumour assessments will be conducted according to RECIST1.1 and will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. A CT or MRI scan of the brain is required if there is a clinical suspicion of CNS metastases. Disease status during maintenance treatment will be determined based on comparison with the tumour assessment done at the end of induction treatment. Up to and including May 31, 2019, tumour assessments will be conducted every 8 weeks from the start of maintenance treatment regardless of treatment delays. After May 31, 2019, disease status will not be collected for the study and tumour assessments may be conducting per local practice. Patients who discontinue study treatment during the Maintenance Treatment Phase prior to disease progression will also continue to be followed for progressive disease, with disease assessments per RECIST 1.1 conducted every 8 weeks until progression or May 31, 2019, whichever comes first.
Tumour assessments
xannot-068 68
T4:t
1
Adverse events will be documented at every cycle during treatment. Patients in the experimental arm of Cohort 3 will be followed for new AEs for 90 days following the discontinuation of study treatment. Patients in the control arm will be followed for new AEs for 28 days following the discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed until the event resolves, the Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws consent. Death related to disease progression is not considered to be an SAE. The Sponsor should be notified if the Investigator becomes aware of any SAE or AEs of special interest occurring after the end of the adverse event reporting period if the event is believed to be related to prior study treatment.
Adverse events (including SAEs)
xannot-069 69
T4:u
1
Patients in the experimental arm will receive capecitabine 1000 mg/m2 b.i.d. Days 1-14 followed by a one-week treatment break for every 3-week treatment cycle. Capecitabine dose calculations by body surface area with corresponding tablet counts are provided in Appendix 7. Trastuzumab will be administered by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses. Pertuzumab will be administered by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses. Patients in the control arm will receive: 5-FU or capecitabine, dose and schedule will be according to local label, where applicable, or otherwise will be determined per the Investigator’s discretion, with bevacizumab 5 mg/kg via 15 – 30 minute IV infusion on Day 1 of every 2-week cycle. If a control arm patient receives capecitabine administered according to a 3- week cycle, timing of all study procedures and assessments scheduled according to 2-week control arm treatment cycles (e.g. ECOG performance status) will be defined by the treatment cycles of concurrently administered bevacizumab.
Study medication administration
Appendix 7
xannot-070 70
T5:c
1
After discontinuation of study treatment and the Study Treatment Discontinuation Visit, patients will enter the Post-Treatment Follow-up Phase. Beginning after the Study Treatment Discontinuation Visit, patients will be followed up every 3 months. Up to and including May 31, 2019, follow-up will include disease status (patients discontinuing study treatment prior to disease progression only), in addition to safety evaluations and recording of subsequent anti-cancer therapies and survival. After May 31, 2019, disease status will not be collected for the study. Treatment during the Post-Treatment Follow-up Phase is at the Investigator’s discretion, however, patients treated with atezolizumab should not receive other immunomodulatory agents for 10 weeks after study treatment discontinuation. Patients who discontinue study treatment prior to disease progression will be followed for PFS, with disease status followed every 8 weeks until progression or May 31, 2019, whichever comes first.
Vital signs include measurements of systolic and diastolic blood pressure while the patient is in a seated position, and temperature. Experimental arm only: For the first atezolizumab infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressures, and temperature) should be determined within 60 minutes before the infusion, every 15 ± 5 minutes during the infusion, and 30 ± 10 minutes after the infusion. For subsequent infusions, vital signs will be collected within 60 minutes before the infusion and should be collected during or after the infusion if clinically indicated or if symptoms occurred in the prior infusion. Vital sign measurements from every second treatment cycle only will be recorded in the eCRF.
Vital signs and weight
xannot-072 72
T5:k
1
Haematology includes haemoglobin, haematocrit, platelet count, red blood cell count, white blood cell count, and differential. Blood chemistry includes ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, blood urea nitrogen or urea, LDH, creatinine, glucose, calcium, phosphorus, sodium, potassium, chloride, bicarbonate. For experimental arm only patients, blood chemistry will also include magnesium, creatine phosphokinase, lipase and amylase. Haematology and blood chemistry tests must be conducted prior to treatment administration on Day 1 of each treatment cycle with the results available for review prior to start of treatment according to local standards for treatment management. Clinical laboratory results from every second cycle only will be recorded in the CRF. Clinical laboratory results constituting a clinically significant AE should be recorded as such.
Haematology and blood chemistry
xannot-073 73
T5:m
1
Urinalysis must be performed by dipstick within 48 hours prior to every treatment cycle. A 24-hour urine collection is needed in the event of proteinuria ≥ ± 2 by dipstick test. Urinalysis results from every second cycle only will be recorded in the CRF.
Urinalysis (dipstick)
xannot-074 74
T5:o
1
Patients with active tuberculosis are not eligible for Cohort 4 and will be excluded from entering the Maintenance Phase of the study. Investigators must confirm absence of active disease in patients with a positive test.
Tuberculosis test
xannot-075 75
T5:p
1
HIV testing performed in accordance with national and/or institutional guidelines. HBV serology includes HBsAg and anti-HBc. HCV serology includes anti-HCV. Results required to determine eligibility for Cohort 4.
HIV, HBV, HCV serology
xannot-076 76
T5:q
1
LVEF must be assessed in all Cohort 4 patients prior to randomization. Only experimental arm patients require subsequent LVEF monitoring which should be conducted every 6 cycles after Cycle 4. In addition, if any experimental arm patient develops clinical signs or symptoms suspicious of cardiac failure they should undergo an LVEF assessment without delaying until the next scheduled assessment (i.e. if indicated prior to the next scheduled assessment). For experimental arm patients who restart cobimetinib following a delay due to asymptomatic or symptomatic LVEF decrease, LVEF must be assessed at 2, 4, 10, and 16 weeks, then every 6 cycles after restarting treatment (see Appendix 16). Evaluation of LVEF must be performed by the same method (ECHO or MUGA) for each patient. It is strongly encouraged that the same laboratory and operator perform ECHO/MUGA scans for each individual patient. The treatment discontinuation visit evaluation of LVEF does not need to be performed at the treatment discontinuation visit if an evaluation has been performed within the last 12 weeks and there are no clinically significant findings and/or changes from baseline.
LVEF
Appendix 16
xannot-077 77
T5:r
1
If an ophthalmology exam was done within 12 weeks of the discontinuation visit and was normal, it does not need to be repeated.
Ophthalmology exam
xannot-078 78
T5:s
1
Up to and including May 31, 2019, tumour assessments will be conducted according to RECIST1.1, and additionally according to mRECIST for patients in the experimental arm. Assessments will include radiology, chest and abdominal CT or MRI, and other scans to document all sites of disease. A CT or MRI scan of the brain is required if there is a clinical suspicion of CNS metastases. Disease status during maintenance treatment will be determined based on comparison with the tumour assessment done at the end of induction treatment. Up to and including May 31, 2019, tumour assessments will be conducted every 8 weeks from the start of maintenance treatment regardless of treatment cycle delays. After May 31, 2019, disease status will not be collected for the study and tumour assessments may be conducting per local practice. Tumour assessments for control arm patients will not be collected for study purposes after disease progression per RECIST 1.1 has been documented or May 31, 2019, whichever occurs first. Tumour assessments for experimental arm patients will not be collected for study purposes after disease progression per mRECIST has been documented or May 31, 2019, whichever occurs first. Patients who discontinue study treatment during the Maintenance Treatment Phase prior to disease progression will also continue to be followed for progressive disease, with disease assessments per RECIST 1.1 or mRECIST (as described above) conducted every 8 weeks until progression or May 31, 2019, whichever comes first.
Tumour assessments
xannot-079 79
T5:u
1
Plasma samples will be collected from all patients for exploratory biomarker analyses. These samples will be sent to a designated laboratory. Samples during treatment should be taken within 48 hours prior to study treatment on the days indicated, unless otherwise specified (see Appendix 17 and the Laboratory Manual).
Plasma samples
Appendix 17
xannot-080 80
T5:v
1
Patients in the experimental arm of Cohort 4 will be followed for new AEs for 90 days following the discontinuation of study treatment. Patients in the control arm will be followed for new AEs for 28 days following the discontinuation of study treatment. At the time of treatment discontinuation, any ongoing AE/SAE will be followed until the event resolves, the Investigator assesses the event as stable, the patient is lost to follow-up, dies or withdraws consent. Death related to disease progression is not considered to be an SAE. The Sponsor should be notified if the Investigator becomes aware of any SAE or AEs of special interest occurring after the end of the adverse event reporting period if the event is believed to be related to prior study treatment.
Adverse events (including SAEs)
xannot-081 81
T5:w
1
Patients in the experimental arm will receive cobimetinib 60 mg orally once daily for 3 weeks followed by a 1 week treatment break (21/7 schedule). Treatment cycle length in this arm is 2 weeks. Cobimetinib will be administered daily every day of each odd numbered 2-week treatment cycle, and for the first 7 days only of each even numbered 2-week treatment cycle. Atezolizumab will be administered at a fixed dose of 840 mg administered via 60-minute IV infusion on Day 1 of every 2-week cycle (if initial infusion is well tolerated, subsequent infusions will be done over a 30-minute time period). Patients in the control arm will receive: 5-FU or capecitabine, dose and schedule will be according to local label, where applicable, or otherwise will be determined per the Investigator’s discretion, with bevacizumab 5 mg/kg via 15 – 30 minute IV infusion on Day 1 of every 2-week cycle. If a control arm patient receives capecitabine administered according to a 3- week cycle, timing of all study procedures and assessments scheduled according to 2-week treatment cycles (e.g. ECOG performance status) will be defined by the treatment cycles of concurrently administered bevacizumab.