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response confirmation

To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by consecutive repeat assessments that should be performed no less than 28 days after the criteria for response are first met.  
Overall time point responses for all possible combinations of responses in target and non-target lesions with or without the appearance of new lesion.  
| Table 6. Classification of responses  Target lesions Nontarget lesions                        | New lesions   | Overall response   |    |
|-----------------------------------------------------------------------------------------------|---------------|--------------------|----|
| CR                                                                                            | CR/NA         | No                 | CR |
| CR                                                                                            | SD            | No                 | PR |
| CR                                                                                            | UE/ND         | No                 | UE |
| PR                                                                                            | Non-PD/NA     | No                 | PR |
| PR                                                                                            | UE/ND         | No                 | UE |
| SD                                                                                            | Non-PD/NA     | No                 | SD |
| SD                                                                                            | UE/ND         | No                 | UE |
| PD                                                                                            | Any           | Yes or no*         | PD |
| Any                                                                                           | PD            | Yes or no*         | PD |
| Any                                                                                           | Any           | Yes*               | PD |
| UE                                                                                            | Non-PD/NA     | No                 | UE |
| ND                                                                                            | Non-PD/NA     | No                 | UE |
| NA                                                                                            | SD            | No                 | SD |
| NA                                                                                            | CR            | No                 | CR |
| CR: complete response; PR: partial response SD: stable disease; PD: progressive response; UE: |               |                    |    |  
unable to evaluate (any target or non-target lesion present at baseline which was not assessed or unable to be evaluated leading to an inability to = determine the status of that particular tumor for that time point); NA: not applicable;(no target or nontarget lesions identified at baseline);
ND: not done (scans not performed at this timepoint)
Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time are to be classified as having
"symptomatic deterioration."  
| Table 7. Definition of lesions and imaging modality and their requirement  Definitions Description Measurable lesions Target lesions that can be measured accurately in at  least one dimension (longest diameter to be  recorded) as ≥20 mm with conventional techniques,  or as ≥10 mm with spiral (helical) computed  tomography (CT) scan or two (2) times the  reconstruction interval (RI) when using spiral  (helical) or multidetector CT, but not less than 10  mm.  Non-measurable lesions Non-target lesions not classified as measurable  lesions (longest diameter <20 mm with conventional  techniques or <10 mm with spiral CT scan) and truly  non-measurable lesions. These include bone lesions  on BS, effusions, and leptomeningeal disease. Any  measurable lesions that were not classified as target  lesions will be classified as non-target lesions. Target lesions All measurable lesions up to a maximum of 5 lesions and 2 lesions per organ, representative of all  involved organs, are to be identified as target lesions  and recorded and measured. Target lesions are to be  selected on the basis of their size (those with the  longest diameter) and their suitability for accurate  repeated measurements (either by imaging  techniques or clinically). All lesions other than target lesions (or sites of  disease) are to be identified as nontarget lesions and  are to be recorded. Measurements of these lesions are  not required, but the presence or absence of each is  to be noted.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Definitions        | Description Longest diameter for target lesions - The sum of the  longest diameter for all target lesions (SLD). Complete response - Disappearance of all target  lesions.  Partial response: At least a 30% decrease in the sum  of the longest diameter of target lesions, taking as  reference the Screening sum longest diameter.  Stable disease: Neither sufficient shrinkage to  qualify for partial response nor sufficient increase to  qualify for progressive disease.  Progressive disease: At least a 20% increase in the  sum of the longest diameters of target lesions (with  addition of diameters of any newly emergent  measurable lesions), taking as reference the smallest  sum of the longest diameters (nadir) recorded since  screening. UE/ND/NA   |
|--------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Non-target lesions | All lesions other than target lesions (or sites of  disease) are to be identified as nontarget lesions and  are to be recorded. Measurements of these lesions are  not required, but the presence or absence of each is  to be noted.  Complete response: Disappearance of all nontarget lesions.  Incomplete response/stable disease: Persistence of  one or more non-target lesion(s).  Progressive disease: Unequivocal progression of a  non-target lesion or appearance of 1 or more new  lesions.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |  
| Definitions           | Description UE/ND/NA                                                                                                                                                                                                                                                                                   |
|-----------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Best overall response | The best overall response is the confirmed overall  response. To be assigned a best overall response of  partial response or complete response, change in  tumor measurements must be confirmed by repeat  assessment no less than 4 weeks after the criteria for  response of CR or PR are first met. |
| Methods of            | The same imaging modality, method of assessment,                                                                                                                                                                                                                                                       |
| measurements          | and technique must be used throughout the study to  characterize each identified and reported lesion.  All measurements are to be made with a ruler or  calipers; measurements are to be recorded in metric  notation.                                                                                 |
| Clinical examination  | Clinically detected lesions are only to be considered  measurable when they are superficial (e.g., skin  nodules and palpable lymph nodes). For skin  lesions, documentation by color photography— including a ruler to estimate the size of the lesion— is recommended.                               |
| Chest X-ray           | Lesions on the chest X-ray are to be acceptable as  measurable lesions when they are clearly defined  and surrounded by aerated lung. Chest X ray is to  be performed in full inspiration in the posteranterior projection. The film to tube distance is to  remain constant between examinations. If patients  with advanced disease are not well enough to fulfill  these criteria, such situations are to be reported together with the measurements. Lesions bordering  the thoracic wall, and lesions bordering or                                                                                                                                                                                                                                                                                                        |  
| Definitions            | Description involving the mediastinum, are not suitable for  measurements by chest x-ray.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                               |
|------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------|
| Computed               | Tomography                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | CT is the primary imaging modality of choice. |
| and Magnetic Resonance | Conventional CT and magnetic resonance imaging                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                               |
| Imaging                | (MRI) are to be performed with contiguous cuts of  10 mm or less in slice thickness. Spiral CT is to be  performed by use of a 5mm contiguous  reconstruction algorithm. CT scans of the thorax,  abdomen, and pelvis are to be contiguous throughout  the anatomic region of interest. The minimum size of  the lesion is to be no less than double the slice  thickness.  The longest diameter of each target lesion is to be  selected in the axial plane only. For spiral CT  scanners, the minimum size of any given lesion  at Screening may be 10 mm, provided the images  are reconstructed contiguously at 5 mm intervals. For conventional CT scanners, the minimum-sized  lesion is to be 20 mm by use of a contiguous slice  thickness of 10 mm.  In patients in whom the abdomen and pelvis have  been imaged, oral contrast agents are to be given to  accentuate the bowel against other soft-tissue  masses. Intravenous contrast agents are also to be  given, unless contraindicated for medical reasons  such as allergy. An adequate volume of a suitable  contrast agent is to be given so that the metastases  are demonstrated the best effect. All images from  each examination are to be included and not  selected" images of the apparent lesion. |                                               |  
| Definitions   | Description All window settings are to be included, particularly  in the thorax, where the lung and soft-tissue windows  are to be considered. Lesions are to be measured on  the same window setting on each examination.  When MRI is used, lesions are to be measured in the  same anatomic plane by use of the same imaging  sequences on subsequent examinations. Wherever  possible, the same scanner is to be used.   |
|---------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Bone scan     | Bone scans are to be used for the assessment of nontarget lesions only.                                                                                                                                                                                                                                                                                                                                                                                                                              |
| Ultrasound    | Ultrasound is not to be used to measure tumor lesions  that are clinically not easily accessible.                                                                                                                                                                                                                                                                                                                            |
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15.6. r codes used to

Table 1 is generated with software R 3.4 with BOIN package 2.4. Various scenarios of toxicity distribution with target toxicity rate at different dose levels are generated with dfcrm package.  
Operative characteristics of the study design are also generated with BOIN package. The R script for this study is as follows:
if(!require("pacman")){
install.packages("pacman")}
pacman::p_load(BOIN, dfcrm)
target<-0.3 \# target toxicity rate\# nc<-10 \#number of cohorts cs<-3 \# cohort size nes<- 15 \# number of pts in a cohort for early stop\# sb<-target*0.7 \#set up the safe boundary, narrower than default\# tb<-target*1.3 \#set up the toxic boundary,narrower than default\#
get.boundary(target=target,ncohort=nc, cohortsize = cs, n.earlystop = nes, p.saf =sb, p.tox = tb, extrasafe = FALSE, offset = 0.05) \# get operating characteristics \# use dfcrm to get priors delta<-0.09 \# the acceptable range of DLT mtd0<-3 \# prior MTD, usu. the starting dose\# k<-6 \# number of dose levels p0<-getprior(halfwidth=delta, target=target, nu=mtd0, nlevel=k, model = "empiric")
p1<-round(p0, digits = 2) p1 \# the toxicity probability distribution get.oc(target = target, p.true = p1, ncohort = nc, cohortsize = cs, n.earlystop = nes, p.saf = sb, p.tox = tb, extrasafe = FALSE, ntrial = 1000) \# get operative characteristic
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15.8. pregnancy notification worksheet

| Study No.                                                  | Site No.:                                             | Patient ID No.   | Patient Initial   |
|------------------------------------------------------------|-------------------------------------------------------|------------------|-------------------|
| HLX06FIH Did the patient withdraw from the Study? Yes____. | No._________                                          |                  |                   |
| Sex                                                        | SEX Code: ( ) Female patient ( ) Male patient partner |                  |                   |  
Estimated Date of Conception  
Day Month Year  
Investigational Product Administration Starting Date  
Day Month Year  
Investigational Product Administration Stop Date  
| Day                                              | Month   | Year   |
|--------------------------------------------------|---------|--------|
| FAX to: Henlix Biotech Co. Ltd, Attn: Shufan Lin |         |        |  
| FAX NO. +886-2-27927901   | TEL: +886-2-27927901   |      |
|---------------------------|------------------------|------|
| Day                       | Month                  | Year |
| Investigator Name:        | Tel:                   |      |
| Institution:              | Site No.:              |      |
| Address:                  |                        |      |
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17. references

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