appendix a fact-h&n symptom index
investigator agreement

Subject ID:
Subject Initials:
Date Completed:
FACT/NCCN HNSI
Below is a list of statements that other people with your illness have said are important.  
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
| Not at                                         | A little   | Some-   | Quite   | Very   |    |
|------------------------------------------------|------------|---------|---------|--------|----|
| all                                            | bit        | what    | a bit   | much   |    |
| 2                                              | 3          |         |         |        |    |
| I have pain.                                   | 0          | 1       | 4       |        |    |
| I have a lack of energy                        | 0          | l       | 2       | 3      | 4  |
| I can swallow naturally and easily .........   | 0          | 1       | 2       | 3      | 4  |
| I have pain in my mouth, throat or neck        | 2          | 3       |         |        |    |
| 0                                              | 1          | 4       |         |        |    |
| I have trouble breathing .                     | 0          | i       | 2       | 3      | 4  |
| I am able to communicate with others .         | 2          | 3       |         |        |    |
| 0                                              | 1          | 4       |         |        |    |
| I have nausea                                  | 0          | l       | 2       | 3      | 4  |
| I can eat solid foods                          | 0          | 1       | 2       | 3      | 4  |
| I worry that my condition will get worse       | 0          | l       | 2       | 3      | 4  |
| I am content with the quality of my life right | 0          | l       | 2       | 3      | 4  |
| nn                                             |            |         |         |        |    |  
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| Insident)
Version 4, Copyright 2001                       | 2 April 2020
Page I of I           |            |
|-----------------------|-----------|------------|
| For Internal Use ONLI |           |            |
| Form Completed By:    | - subject | Sign/Date: |
| Comment, if           |           |            |
| applicable:           |           |            |
appendix a fact-h&n symptom index
15.2 appendix b performance status

| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                                 |                                                            |             |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------|------------------------------------------------------------|-------------|
| Grade                                                                                                                                                                                      | Descriptions                                                                | Percent                                                    | Description |
| 100                                                                                                                                                                                        | Normal, no complaints, no  evidence of disease.                             |                                                            |             |
| Normal activity. Fully active, able                                                                                                                                                        |                                                                             |                                                            |             |
| 0                                                                                                                                                                                          | to carry on all pre-disease  performance without restriction.               | Able to carry on normal                                    |             |
| 90                                                                                                                                                                                         | activity; minor signs or  symptoms of disease. Normal activity with effort; |                                                            |             |
| 80                                                                                                                                                                                         | some signs or symptoms of  disease.                                         |                                                            |             |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). |                                                                             |                                                            |             |
| 1                                                                                                                                                                                          | Cares for self, unable to carry                                             |                                                            |             |
| 70                                                                                                                                                                                         | on normal activity or to do  active work. Requires occasional assistance,   |                                                            |             |
| 60                                                                                                                                                                                         | but is able to care for most of  his/her needs.                             |                                                            |             |
| In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                             |                                                                             |                                                            |             |
| 2                                                                                                                                                                                          | Requires considerable                                                       |                                                            |             |
| 50                                                                                                                                                                                         | assistance and frequent  medical care.                                      |                                                            |             |
| 40                                                                                                                                                                                         | Disabled, requires special care  and assistance.                            |                                                            |             |
| In bed >50% of the time.  Capable of only limited self-care,  confined to bed or chair more  than 50% of waking hours.                                                                     |                                                                             |                                                            |             |
| 3                                                                                                                                                                                          | Severely disabled,                                                          |                                                            |             |
| 30                                                                                                                                                                                         | hospitalization indicated. Death  not imminent.                             |                                                            |             |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                   | 20                                                                          | Very sick, hospitalization  indicated. Death not imminent. |             |
| 4                                                                                                                                                                                          | 10                                                                          | Moribund, fatal processes  progressing rapidly.            |             |
| 5                                                                                                                                                                                          | Dead.                                                                       | 0                                                          | Dead.       |  
| 15.3                                                                                  | Appendix C: Study Calendar (Also see Section 8)  Screening Study Treatment   | Follow Up            |      |      |      |
|---------------------------------------------------------------------------------------|------------------------------------------------------------------------------|----------------------|------|------|------|
| 28 Day Cycles 2                                                                       |                                                                              |                      |      |      |      |
| Within 28  days of  registration (except  pregnancy  within 14 days  of registration) | Every 8  weeks 13 Day 28 +/- 7 days (C12+ Optional  q12wks +/- 14d)          | Non-PD  Followup 3                      | PD   |      |      |
| Followup 19                                                                                       |                                                                              |                      |      |      |      |
| q8wks  +/- 2  week                                                                    |                                                                              |                      |      |      |      |
| End Of                                                                                |                                                                              |                      |      |      |      |
| Treatment 1                                                                           |                                                                              |                      |      |      |      |
| Day 1                                                                                 | Day 15                                                                       |                      |      |      |      |
| +/- 3 days                                                                            | +/- 3 days                                                                   | q12wks  +/- 2  weeks |      |      |      |
| Medical History                                                                       | X                                                                            |                      |      |      |      |
| Physical Exam & Vital Signs                                                           | X                                                                            | X                    | X    | X    | Z    |
| Height                                                                                | X                                                                            |                      |      |      |      |
| Weight                                                                                | X                                                                            | X 4                  | X 4  | X    | Z    |
| ECOG Performance Status                                                               | X                                                                            | X                    | X    | X    | Z    |
| CBC with Differential 5                                                               | X                                                                            | X                    | X    | X    | Z    |
| Serum chemistries and Liver  function tests 5                                         | X                                                                            | X                    | X    | X    | Z    |
| Magnesium 5                                                                           | X                                                                            | X                    | X    | X    | Z    |
| Documentation of Corrected  Calcium                                                   | X                                                                            |                      |      |      |      |
| Research (correlatives) blood                                                         | X 6                                                                          | X 7                  | X    | X 8  |      |
| Pregnancy test                                                                        | X 9                                                                          |                      |      |      |      |
| Research biopsy 10                                                                    | X                                                                            |                      |      |      |      |
| Confirmation of availability of  archived diagnostic specimens                        | X 11                                                                         |                      |      |      |      |
| Tumor measurements,  RECIST 1.1 (CT or MRI) 12                                        | X                                                                            | X 13                 | X    | Z    |      |
| FACT-H&N Symptom Index                                                                | X 6                                                                          | X 14                 | X 14 |      |      |
| Tobacco Assessment                                                                    | X 6                                                                          |                      |      |      |      |
| Oropharyngeal & unknown  primary cases, p16 Status 15                                 | X                                                                            |                      |      |      |      |
| Registration/Randomization                                                            | X                                                                            |                      |      |      |      |
| Cetuximab                                                                             | X                                                                            | X                    |      |      |      |
| Ficlatuzumab                                                                          | X                                                                            | X                    |      |      |      |
| Concomitant medication review                                                         | X                                                                            | X                    | X    | X    |      |
| Adverse event evaluation                                                              | X                                                                            | X                    | X 16 | X 17 | X 18 |
| Survival assessment                                                                   | X                                                                            | X 19                 |      |      |      |  
1 The End of Treatment visit should be performed as soon as possible, but preferably within 30 days after the offtreatment decision date. Procedures will be performed if not performed in the previous 14 days, except tumor measurements should only be performed if not performed in the previous 28 days and only if it is an appropriate standard of care procedure.  
2 Refer to Section 5.5.1 which addresses scheduling when there are missed and/or skipped visits due to treatment delays or other.  
3 Procedures indicated with "Z" are not required to be performed for the research, but if they are performed for standard of care, the data will be collected. Patients who initiate a new line of antineoplastic therapy will be censored for progression at that time point; research blood will be drawn and they will be followed per the progressive disease follow-up schedule. 4 For both agents: Recalculate the doses of both ficlatuzumab and cetuximab only if there is a ≥ 10% change in weight. Exception: If, in the opinion of the treating investigator, weight change of ≥ 10% is due to edema, recalculation of the ficlatuzumab dose is not required. This decision must be clearly documented. Refer to Section 5. 5 May be performed on the day of, or within the 3 days prior to study treatment.  
6 May be performed during screening, or prior to drug administration on Cycle 1, Day 1. 7 For convenience, research blood may be drawn simultaneously with pre-treatment labs for the next cycle. Subjects who transition to every-12-week tumor assessments will have the research *blood drawn every 12 weeks, consistent* with the tumor assessment schedule. Refer to Section 8.3.3 8 Research blood will be obtained at the time of disease progression or censored for progression (see footnote 3 above, and Section 8.5.2) during the follow up period, then followed per the progressive disease follow up. 9 A negative pregnancy test is required in women of child-bearing potential within 14 days prior to registration.  
Negative pregnancy test must be confirmed again within 3 days prior to first drug administration. 10 Archived tumor tissue, preferably the most recent tissue available, may be substituted if the biopsy is not safe and/or feasible, and/or would present unacceptable clinical risk, and the Sponsor has approved omission of the baseline biopsy. See Section 9.2. 11 Archived tissue, preferably primary tumor tissue blocks (or slides, if blocks are not available) from procedures prior to clinical cetuximab exposure. This is not an eligibility requirement and subjects can be randomized without this confirmation.  
12 For scheduling convenience, tumor measurements may occur on day 1 of the following cycle, so long as the scan is done and results are known **prior** to drug administration. 13 Tumor measurements must be performed every 8 weeks, +/- 7 days, regardless of any delay that occurs within the prior 2 cycles. S*ubjects who remain on treatment past Cycle 12 can transition to tumor assessments being* performed every 12 weeks, +/- 14 days. Refer to Section 8.3.3. 14 FACT-H&N Symptom Index will be performed at baseline and at the end of cycle 2 and cycle 6 only, or when the subject is censored for progression after C4D28 but before C6D28 (see EOT procedures). For scheduling convenience, FACT-H&N Symptom Index may be completed on day 1 of the following cycle or at the EOT visit. 15 For oropharyngeal & unknown primary, p16 status must be established, if not previously known, before randomization.  
16 Subject will be followed for AEs/SAEs for 60 days **after last dose of study drug** or until the initiation of subsequent antineoplastic therapy, whichever is earlier. (Refer to protocol Section 8.5.1 for important and specific details on collection and follow up of AEs.)
17 Subjects who end treatment **due to a reason other than progressive disease** will have an AE assessment at the first follow-up visit. (Refer to protocol Section 8.5.1 for important and specific details on collection and follow up of AEs.)
18 Subjects who end treatment **due to progressive disease** will have an AE assessment at least 60 days after last dose of study drug. (Refer to protocol Section 8.5.1 for important and specific details on collection and follow up of AEs.)
19 Subjects will be followed for survival for 2 years after disease progression.
appendix a fact-h&n symptom index
15.4 appendix d tobacco use

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