Follow-up of Cancer Patients Receiving Immune Checkpoint Inhibitor Therapy by Electronic Patient Reported Outcomes-tool
Phase: NA
Conditions: Cancer
Sponsor: Oulu University Hospital

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Clinical Trial Protocol 
 
Study 
Follow-up of Cancer Patients Receiving Immune Checkpoint Inhibitor Therapy by Electronic 
Patient Reported Outcomes-tool (KISS) 
 
Principal Investigator: Jussi Koivunen 
 
Oulu University Hospital, Dept of Oncology and Radiotherapy 

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OUTLINE: 
Study: 
Follow-up of Cancer Patients Receiving Immune Checkpoint 
Inhibitor Therapy by Electronic Patient Reported Outcomes-
tool 
Protocol version 
11.2.2019 
Sponsor 
Jussi Koivunen, Oulu University Hospital 
Indication 
Cancer Patients Receiving Immune Checkpoint Inhibitor 
Therapy 
Outcomes 
 
1. Patient reported symptoms and their severity  
2. Number of triggered alerts by the tool and their 
correlation to treatment side-effects, cancer 
progression, other medical events or survival 
3. Correlation between different symptoms and to 
treatment side-effects, cancer progression, other 
medical events or survival 
4. QoL of patients using QLQ-C30 and their correlation to 
treatment side-effects, cancer progression, other 
medical events or survival  
5. Patient compliance using KaikuHealth e-questionnaire 
and response rates to symptom and QLQ-C30 
questionnaires  
6. Correlation of baseline laboratory values to treatment 
side-effects, cancer progression, other medical events 
or survival. 
Study design 
Prospective one-arm study 
Study size 
40 patients 
Criteria 
Inclusion criteria:  
1. Signed informed consent 
2. Advanced cancers 
3. Immune checkpoint inhibitor therapy initiated within 
+/- 2wks 
4. Age >18y 
5. ECOG 0-3 
6. Patient compliant with the study procedures  
Exclusion criteria: 
1. Immune checkpoint inhibitor therapy initiated > 2wks 
ago 
2. General vulnerability affecting the participation in the 

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trial 
3. No internet access 
Study procedures 
Patient: 
1. Answers 
17 
question 
Kaiku 
immunological 
treatment 
side-effects 
questionnaire 
before 
initiation of the treatment or within 2 weeks and 
thereafter weekly up to disease progression or 24 
weeks 
2. Answers QLQ-C30 QoL questionnaire before initiation 
of the treatment or within 2 weeks and thereafter every 
four weeks up to disease progression or 24 weeks 
3. Answers Patient Experience survey every four weeks 
up to disease progression or 24 weeks 
Doctor: 
1. Fills Kaiku baseline patient information before the 
initiation of treatment or within 2 weeks 
 
2. Fills Kaiku follow-up information 6-12 weeks 
frequency up to disease progression or 24 weeks 
Study End-points  
1. Patient reported symptoms and their severity  
2. Number of triggered alerts by the tool and their 
correlation to treatment side-effects, cancer 
progression, other medical events or survival 
 Gr2 alerts 
 Gr3-4 alerts 
3. Correlation between different symptoms and to 
treatment side-effects, cancer progression, other 
medical events or survival 
4. QoL of patients using QLQ-C30 and their correlation to 
treatment side-effects, cancer progression, other 
medical events or survival  
5. Patient compliance using KaikuHealth e-questionnaire 
and response rates to symptom and QLQ-C30 
questionnaires  
6. Correlation of baseline laboratory values to treatment 
side-effects, cancer progression, other medical events 
or survival. 
Study course 
After signing of the informed consent, patient is trained on use 
of Kaiku software. Patient answers questionnaires 1-4 week 
frequencies up to 24 weeks. Patients survival is followed after 
24 week period. 
Study doctor fills baseline information and thereafter follow-
up information 6-12week frequency up to 24weeks.  

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Sample size 
Sample size of the study is 40 and study patients are expected 
to be recruited within 2 years. 
Study time 
Q2/2017-Q4/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 1.  Study procedures  
 
Baseline 
Immunological Therapy period 
Follow-up 
Schedule 
≤ 2vk prior 1st 
immunological 
therapy 
infusion or 
≤2vko after 
Weekly 
q4w  
q6-12w 
 
 
Written Informed 
consent 
X 
 
 
 
 
KaikuHealth 
immunological 
treatment side-effects 
questionnaire 1,3 
X 
X 
 
 
 
KaikuHealth QLQ-
C30,3 
X  
 
X 
 
 
KaikuHealth baseline 
patient information 2 
X 
 
 
 
 
KaikuHealth follow-up 
information 2,3 
 
 
 
X 
 
Patient survival 
follow-up4 
 
 
 
 
X 
Kaiku Patient 
experience 
questionnaire ¹ 
 
 
X 
 
 
 
(1) Patient fills 
(2) Doctor fills 
(3) Up to 24 wks 
(4) Up to 12 mo 
 
 
 
 

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TABLE OF CONTENTS 
PAGE 
AMENDMENTS 
7 
1. 
BACKGROUND 
7 
IMMUNO-ONCOLOGICAL TREATMENTS 
7 
STUDY RATIONALE 
8 
2. 
STUDY OBJECTIVES 
8 
3. 
STUDY DURATION 
9 
4. 
PATIENT SELECTION 
9 
STUDY POPULATION 
9 
INCLUSION CRITERIA 
9 
EXCLUSION CRITERIA 
9 
7. 
STUDY NATURE 
9 
STUDY FORM 
9 
STUDY PROCEDURES 
9 
BASELINE 
10 
TREATMENT PERIOD 
10 
FOLLOW-UP PERIOD 
10 
8. 
STUDY INSTRUMENTS 
10 
KAIKUHEALTH QUESTIONNAIRES 
10 
KAIKUHEALTH IMMUNOLOGICAL TREATMENT SIDE-EFFECTS QUESTIONNAIRE 
11 
9. 
MONITORING 
11 
10. 
STATISTICAL PLAN 
11 
POWER ASSESSMENT 
11 
SAFETY ASSESSMENT 
12 
11. 
SIGNATURE 
12 
12. 
REFERENCES 
13 

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AMENDMENTS 
Amendment 
number 
Amendment 
date 
Protocol 
versio nro 
Amendment type 
Amendment nature/purpose 
1.1 
9.11.2017 
1.1 
Protocol change 
Open form-question excluded 
from the side-effect 
questionnaire 
1.12 
23.11.2018 
1.1 
Patient 
Information and 
Informed Consent 
translation 
Translation of patient 
documents to swedish and 
english.  
1.2 
28.1.2019 
1.2 
Protocol change 
Study end-points, analysis of 
the results, side-effect 
questionnaire background and 
study duration were redefined 
 
 
1. BACKGROUND 
Immuno-oncological treatments 
It has been known for years that immune system can resist or eradicate malignant 
tumors. However, efficient therapeutic approaches to enhance immune effect on tumors 
have been missing. In past five years, there has been huge development in cancer 
immunotherapies with introduction of immune checkpoint therapies such as PD-(L)1 
and CTLA-4 antibodies. Immune checkpoint inhibitor therapies have become the most 
important therapies in many malignancies such as melanoma, non-small cell lung cancer, 
and urogenital cancers.  
The effect of immune checkpoint inhibitors is mediated by inhibition of T-cell blocking 
which results in T-cell mediated cancer cell death. The side-effects of the immune 
checkpoint inhibitors also relate to the mechanism of action with activated T-cells 
attacking health tissues.  
The side-effects of immune checkpoint inhibitors resemble autoimmune disease. The 
most common side-effects are skin rash, endocrine toxicity, gastrointestinal(GI) toxicity, 
hepatitis, pneumonitis, nephritis, and myositis. Some of the side-effects can be life-
threating. In most cases however, early detection, delaying or stopping immune 
checkpoint therapy, and initiation of immunosuppressive medication (corticoids) can 
resolve or prevent further worsening of side-effect. As general rule, in the occurrence of 
NCI-CTCAE gr2 side-effects immune checkpoint inhibitor therapy is delayed until they 
resolve while in gr3-4 side-effects therapy is discontinued and corticoid therapy is 
initiated.      
Timing of side-effects differs from traditional cancer therapy and they can occur from 
months to years after therapy initiation or after discontinuation of the therapy. 
Therefore, long-term follow-up of patients is warranted even after the therapy 
discontinuation. 

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Study rationale 
Patient reported outcomes (PROs) consist of health-related questionnaires filled by the 
patients themselves which can capture symptoms and signs and their severity. PROs can 
be captures by traditional paper questionnaires or by Web-based approaches. Web-
based reporting of PROs has many advantages compared to paper questionnaires such 
as reducing timely and locational limitations. These advantages make web-based PRO 
capturing more likely to allow changes in symptoms or quality of life (QoL). 
Furthermore, web-based PROs can be coupled to urgency algorithm which sends an 
alert to the care unit on severe or altering symptoms of a patient. This enables rapid 
reaction and treatment of important medical events.  
ePROs have been studied in oncological care. An American randomized study has 
investigated use of ePROs coupled with urgency algorithm in the follow-up of patients 
receiving chemotherapy as palliative treatment of multiple tumor types. Use of ePROs 
resulted in improvement of QoL, decreased ER visits, and improvement of overall 
survival. Another French study has investigated use of urgency algorithm coupled ePROs 
in follow-up of lung cancer patients  compared to traditional follow-up with more 
frequent assessments using physician visits and scans. ePRO follow-up resulted in better 
QoL, improved ECOG status and more active cancer treatments at disease relapse, and 
improved survival 
Immune checkpoint inhibitors differ from traditional cancer therapies with potential 
severe side-effects rising from all the organs of the body and late timing of the side-
effect occurrence.  Therefore, there is a need for comprehensive and long-lasting 
assessment of symptoms. ePROs provide unique and cost-effective means to capture 
broad changes in patients’ symptoms for extended time periods. Since ePRO follow-up 
has been shown to improve survival and QoL of lung cancer patients and cancer patients 
receiving chemotherapy, it is feasible to speculate that ePROs could also improve these 
in cancer patients receiving immune checkpoint inhibitors.  
 
2. STUDY OBJECTIVES 
Objectives: 
1. Spectrum of patient reported symptoms and their severeness  
2. Correlation of urgency algorithm alerts triggered by KaikuHealth immunological 
treatment side-effects questionnaire to investigator assessed iAEs, other relevant  
medical events, tumor progression, and survival  
a. Gr2 alarms 
b. Gr3-4 alarms 
3. Correlation of PROs to investigator assessed iAEs, tumor progression, other 
relevant medical events and survival 
4. Correlations between PROs 
5. Changes in QoL according to KaikuHealth QLQ-C30 questionnaire and their 
correlation to immunological treatment response, AEs, other medical condition 
and survival 
6. Patient compliance to Kaiku ePRO surveillance during treatment period 
according to response rates of Patient experience questionnaire, KaikuHealth 

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immunological treatment side-effects questionnaire and KaikuHealth QLQ-C30 
questionnaire  
7. Correlation of baseline laboratory values to iAE, tumor progression, other 
medical condition and survival 
 
3. STUDY DURATION 
Patient recruiting started 28.6.2017, and the last visit of the last study patient is 
estimated to happen in December 2019. The enrolment period is estimated to be 12 
months. The study will consist a treatment phase, and a post-treatment period (up to 
12months). Survival data will also be collected. The collection of the survival data of a 
patient is limited to 12 months from the study entry. 
 
4. PATIENT SELECTION 
Study population 
Sample size of the study is 40 and study patients are expected to be recruited within 24 
months. 
Inclusion criteria 
1. Written informed consent before any study procedures 
2. Advanced cancer 
3. Initiation of immune checkpoint inhibitor containing therapy ≤2 weeks from the 1sts 
infusion  
4. Age 18  
5. Performance status: ECOG 0-3 
6. Patient is willing and able to comply with treatment and trial instructions 
Exclusion criteria 
1. Initiation of immune checkpoint inhibitor therapy  >2 weeks prior to written 
informed consent 
2. Any medical condition that the Investigator considers significant to compromise the 
safety of the patient or that impairs the interpretation of study assessments 
3. No internet access or email available  
 
 
7. STUDY NATURE 
Study form 
A prospective one-arm multicenter observational study. 
Study procedures  
See Table 1 at page 5. 

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Baseline 
A signed informed consent from every patient must be present before any study 
procedures. 
The parameters listed below are collected at baseline: 
 Demographics (age, gender, weight, hight) 
 ECOG performance status 
 Type of immunological treatment (label, indication, day of the 1st infusion) 
 Blood sampling to measure the following  (blood cell counts: leucocytes, 
neutrophils, lymphocytes, thrombocytes; B-haemoglobin, P-creatinine, ALT, ALP, 
AST, bilirubin, P-LD, P-CRP) 
 Prior autoimmune disease and their treatment 
 KaikuHealth immunological treatment side-effects questionnaire and 
KaikuHealth QLQ-C30 questionnaire filled ≤ 2weeks from 1st infusion 
Treatment period  
Study treatment period lasts the treatment phase of immune checkpoint inhibitor or up 
to 24 weeks.  
The parameters listed below are collected during the treatment phase: 
 KaikuHealth immunological treatment side-effects questionnaire ≤2 weeks from 
the 1st infusion and weekly after that 
o Questionnaireof 17 questions assessing symptoms and their severeness  
 KaikuHealth QLQ-C30 questionnaire ≤ 2weeks from the 1st infusion and every 
four weeks after that 
 Kaiku patient experience questionnaire monthly  
 KaikuHealth follow-up information in 6-12 weeks cycle 
o Urgency algorithm alerts (grade, date, cause of the alert) 
o irAE (type, date, related urgency alert if present) 
o Treatment of irAE (type, date) 
o Unscheduled health care contacts (ER, oncology department, 
appointments and phone calls, reason, date) 
o Treatment response (CR, PR, SD, PD, NE, date) 
o Date of death 
Follow-up period 
During follow-up period patient survival data will be collected from healthcare patient 
records or other electronical sources. 
 
8. STUDY INSTRUMENTS 
KaikuHealth questionnaires 
Study patients will receive a short (5-15min) training on how to use Kaiku software by 
study physician or nurse. The training will include how the sign in to the system, login, 

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navigation in Kaiku software, filling of ePRO questionnaires, function of urgency 
algorithms, messaging, and access email-address for technical assistance. Care unit will 
do the initial registration of the patient. KaikuHealth-service will send email reminders 
to fill in KaikuHealth questionnaires in prescheduled time line. First notification will be 
sent immediately when patient is registered to the study and weekly thereafter. If a 
patient doesn’t fill an ePRO questionnaire promptly, an email remainder is sent three 
days later. If patient doesn’t fill PRO questionnaire within six days, weekly PRO 
assessment will be missed, and notification of new PRO assessment period will be 
initiated with a new email notification seven days after previous. Patient data will stored 
on a server located in Finland. Anonymization will take place when data is analyzed. 
KaikuHealth immunological treatment side-effects questionnaire 
KaikuHealth ePRO follow-up module consists of 17 symptom questionnaire which will 
assess both presence and severity of the symptom. The symptoms selected for the Kaiku 
Health symptom tracking tool for cancer immunotherapy are based on the most 
common adverse events that have occurred during clinical trials of anti-PD1, anti-PDL1 
and anti-CTLA4 immune checkpoint inhibitor monotherapies. The symptoms tracked by 
the instrument are potential signs and symptoms of immune-related adverse events. 
The symptom selection is based on the reported publications of following clinical trials: 
CheckMate 017, CheckMate 026, CheckMate 057, CheckMate 066, CheckMate 067, 
KEYNOTE-010, and OAK. FDA labels for Nivolumab, Pembrolizumab and Atezolizumab 
were also used in the symptom selection for the instrument. The questions for each 
symptom in the instrument were developed based on NCI-CTCAE v.4.03 register by 
converting the description of gradings into a patient-friendly language. 
If algorithm analysis suggests a presence of grade 3 or higher symptom, alert will be 
sent to the care unit after which care unit contacts the patients and if necessary, further 
investigation and/or assessments will be ordered. It is recommended that care unit 
reacts to alerts promptly but no later than three days after an alert. Contact to the 
patient can be made by messaging properties of Kaiku software or phone call.  
Furthermore, patients are informed that Kaiku ePRO follow-up is intended for non-
urgent manners.   
9. MONITORING 
Written informed consents are monitored by an independent single monitor in three 
months cycles. 
 
10. 
STATISTICAL PLAN 
Power assessment 
Due to the study nature (one-arm study) statistical plans are not calculated. 
Approximately 15% of patients receiving immune checkpoint inhibitor therapies have 
been reported to have severe grade 3-4 side-effects, and about 30% face lower grade 
adverse events. In a patient cohort of 40, three to six patients will experience a severe 
iAE. It is estimated that the expected study population is sufficient to evaluate the 
feasibility of the symptom questionnaire in detecting severe adverse events, and 
directing patients to further investigations. Questionnaires from several timepoints are 
estimated to be collected from 90% of study population (~35 patients) which will 

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enable a more comprehensive assessment of feasibility, patient experience and 
correlation of ePRO changes to treatment response and survival.  
Data analysis 
Data analysis will be carried out when the length of follow-up time of the last recruited 
patient is at least 12 weeks. For the final analysis statistical methods will be redefined 
based on actual distributions. 
Safety assessment 
The frequency of iAE not leading to Kaiku urgency alerts is the most important study 
related serious adverse event. 
 
11. 
SIGNATURE 
I promise to carry out investigation according to study protocol, good clinical practice 
and appropriate legislation.  
 
 
Principal investigator and sponsor: 
 
Date 
Signature 
Oulu, 11.2.2019 
___________________ 
__________________________________ 
Jussi Koivunen, adjuvant professor, medical oncologist 
Oulu University Hospital, Dept of Oncology and 
Radiotherapy 
 
 
 
 
 
 

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12. 
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Web Application. Am J Clin Oncol 2017 Oct;40(5):464-469. 
Puzanov I, Diab A, Abdallah K, Bingham CO,3rd, Brogdon C, Dadu R, et al. Managing 
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from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working 
Group. J Immunother Cancer 2017 Nov 21;5(1):95-017-0300-z. 
Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of 
toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, 
treatment and follow-up. Ann Oncol 2017 Jul 1;28(suppl_4):iv119-iv142. 
Wang Dy, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal Toxic Effects 
associated With Immune Checkpoint Inhibitors : A Systematic Review and Meta-analysis. 
JAMA Oncology Published online September 13, 2018. 
doi:10.1001/jamaoncol.2018.3923