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          "row_position": 24
        }
      ]
    },
    {
      "annotation_marker": "d",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 3
        }
      ]
    },
    {
      "annotation_marker": "e",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 5
        }
      ]
    },
    {
      "annotation_marker": "f",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 6
        }
      ]
    },
    {
      "annotation_marker": "g",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 7
        }
      ]
    },
    {
      "annotation_marker": "h",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 8
        }
      ]
    },
    {
      "annotation_marker": "i",
      "annotation_type": "source_note",
      "annotation_text": "See Appendix 8.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 9
        }
      ]
    },
    {
      "annotation_marker": "j",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 10
        }
      ]
    },
    {
      "annotation_marker": "k",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 11
        }
      ]
    },
    {
      "annotation_marker": "l",
      "annotation_type": "footnote",
      "annotation_text": "INR and aPTT only for patients receiving anticoagulants while on protocol-specified treatment.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 12
        }
      ]
    },
    {
      "annotation_marker": "m",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 13
        }
      ]
    },
    {
      "annotation_marker": "n",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 14,
          "method": "synthesized"
        }
      ]
    },
    {
      "annotation_marker": "o",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 15
        }
      ]
    },
    {
      "annotation_marker": "p",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 16
        }
      ]
    },
    {
      "annotation_marker": "q",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 17
        }
      ]
    },
    {
      "annotation_marker": "r",
      "annotation_type": "footnote",
      "annotation_text": "Supplemental Biomarker Program closed as of May 2018. Collection of these samples has been discontinued (see Appendix 18).",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 18
        }
      ]
    },
    {
      "annotation_marker": "s",
      "annotation_type": "footnote",
      "annotation_text": "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).",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 19
        }
      ]
    },
    {
      "annotation_marker": "t",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 21
        }
      ]
    },
    {
      "annotation_marker": "u",
      "annotation_type": "footnote",
      "annotation_text": "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.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 22
        }
      ]
    },
    {
      "annotation_marker": "n1",
      "annotation_type": "footnote",
      "annotation_text": "Supplemental Biomarker Program closed as of May 2018. Collection of these samples has been discontinued.",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 18,
          "method": "synthesized"
        },
        {
          "table_number": 4,
          "location_type": "activity_name",
          "row_position": 20,
          "method": "synthesized"
        }
      ],
      "annotation_text_source": {
        "method": "visual_transcription",
        "note": "Text printed in the source cell (activity label sub-line or header cell) on an image page; marker synthesised."
      }
    },
    {
      "annotation_marker": "pr1",
      "annotation_type": "source_note",
      "annotation_text": "See Appendix 19",
      "marker_locations": [
        {
          "table_number": 4,
          "location_type": "schedule_cell",
          "row_position": 2,
          "column_position": 5,
          "method": "synthesized"
        }
      ],
      "annotation_text_source": {
        "method": "visual_transcription",
        "note": "Text printed in the source cell (activity label sub-line or header cell) on an image page; marker synthesised."
      }
    }
  ],
  "review_items": []
}