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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.", "marker_locations": [ { "table_number": 2, "location_type": "schedule_cell", "row_position": 1, "column_position": 3 } ], "annotation_text_source": { "method": "visual_transcription", "note": "Footnote printed inside the page image (no text layer) on p176; transcribed from a 200 dpi render." } }, { "annotation_marker": "b", "annotation_type": "footnote", "annotation_text": "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.", "marker_locations": [ { "table_number": 2, "location_type": "schedule_cell", "row_position": 1, "column_position": 4 } ], "annotation_text_source": { "method": "visual_transcription", "note": "Footnote printed inside the page image (no text layer) on p176; transcribed from a 200 dpi render." } }, { "annotation_marker": "c", "annotation_type": "footnote", "annotation_text": "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.", "marker_locations": [ { "table_number": 2, "location_type": "schedule_cell", "row_position": 1, "column_position": 5 }, { "table_number": 2, "location_type": "activity_name", "row_position": 26 }, { "table_number": 2, "location_type": "activity_name", "row_position": 27 } ], "annotation_text_source": { "method": "visual_transcription", "note": "Footnote printed inside the page image (no text layer) on p176; transcribed from a 200 dpi render." } }, { "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 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.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 3 } ], "annotation_text_source": { "method": "visual_transcription", "note": "Footnote printed inside the page image (no text layer) on p176; transcribed from a 200 dpi render." } }, { "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": 2, "location_type": "activity_name", "row_position": 5 } ], "annotation_text_source": { "method": "visual_transcription", "note": "Footnote printed inside the page image (no text layer) on p176; transcribed from a 200 dpi render." } }, { "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": 2, "location_type": "activity_name", "row_position": 6 } ], "annotation_text_source": { "method": "visual_transcription", "note": "Footnote printed inside the page image (no text layer) on p176; transcribed from a 200 dpi render." } }, { "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.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 7 } ], "annotation_text_source": { "method": "visual_transcription", "note": "Footnote printed inside the page image (no text layer) on p176; transcribed from a 200 dpi render." } }, { "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": 2, "location_type": "activity_name", "row_position": 8 } ], "annotation_text_source": { "method": "visual_transcription", "note": "Footnote printed inside the page image (no text layer) on p176; transcribed from a 200 dpi render." } }, { "annotation_marker": "i", "annotation_type": "footnote", "annotation_text": "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.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 9 } ], "annotation_text_source": { "method": "visual_transcription", "note": "Footnote printed inside the page image (no text layer) on p176; transcribed from a 200 dpi render." } }, { "annotation_marker": "j", "annotation_type": "footnote", "annotation_text": "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.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 10 } ], "annotation_text_source": { "method": "visual_transcription", "note": "Footnote printed inside the page image (no text layer) on p176; transcribed from a 200 dpi render." } }, { "annotation_marker": "k", "annotation_type": "footnote", "annotation_text": "Evaluation to be performed by a dermatologist, the Investigator or other qualified physician.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 11 } ] }, { "annotation_marker": "l", "annotation_type": "footnote", "annotation_text": "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.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 12 } ] }, { "annotation_marker": "m", "annotation_type": "source_note", "annotation_text": "See Appendix 8.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 13 } ] }, { "annotation_marker": "n", "annotation_type": "footnote", "annotation_text": "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.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 14, "method": "synthesized" } ] }, { "annotation_marker": "o", "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": 2, "location_type": "activity_name", "row_position": 15 } ] }, { "annotation_marker": "p", "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. 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.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 16 } ] }, { "annotation_marker": "q", "annotation_type": "footnote", "annotation_text": "INR and aPTT only for patients receiving anticoagulants while on protocol-specified treatment.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 17 } ] }, { "annotation_marker": "r", "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. Urinalysis results from every second cycle only will be recorded in the CRF.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 18 } ] }, { "annotation_marker": "s", "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 urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 19 } ] }, { "annotation_marker": "t", "annotation_type": "footnote", "annotation_text": "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.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 20 } ] }, { "annotation_marker": "u", "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": 2, "location_type": "activity_name", "row_position": 21 } ] }, { "annotation_marker": "v", "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": 2, "location_type": "activity_name", "row_position": 22 } ] }, { "annotation_marker": "w", "annotation_type": "footnote", "annotation_text": "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.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 24 } ] }, { "annotation_marker": "x", "annotation_type": "footnote", "annotation_text": "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.", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 25 } ] }, { "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": 2, "location_type": "activity_name", "row_position": 21, "method": "synthesized" }, { "table_number": 2, "location_type": "activity_name", "row_position": 23, "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": "n2", "annotation_type": "footnote", "annotation_text": "Experimental Arm only", "marker_locations": [ { "table_number": 2, "location_type": "activity_name", "row_position": 9, "method": "synthesized" }, { "table_number": 2, "location_type": "activity_name", "row_position": 10, "method": "synthesized" }, { "table_number": 2, "location_type": "activity_name", "row_position": 11, "method": "synthesized" }, { "table_number": 2, "location_type": "activity_name", "row_position": 12, "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": [ { "id": "D3", "severity": "medium", "location": { "page": 174 }, "call_made": "Tables 2-5 (Appendices 2-5, maintenance schedules for Cohorts 1, 2, 3, 4) are each typed \"track\" with track_label \"Cohort n\", because each schedules a mutually exclusive biomarker-defined cohort in the Maintenance phase. Table 1 (induction for all patients) is the main_soa.", "alternative": "Type Tables 2-5 as \"main_soa\" (independent schedules) or treat one cohort as the anchor; Cohort 2 and 4 tables also have identical column labels to each other, which a reader could take as \"domain\".", "report_section": "3.1" } ] }