Conditions: Uveal Melanoma
Keywords: Tebentafusp IMCgp100 gp100 metastatic melanoma ImmTAC Immunotherapy Bispecific T cell receptor fusion protein Immune mobilizing monoclonal T cell receptor against cancer UM mUM Kimmtrak
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 146
Healthy volunteers: no

Brief summary:
IMCgp100-102 is a Phase I/II study of the weekly intra-patient escalation dose regimen with IMCgp100 as a single agent in participants with metastatic uveal melanoma (mUM). According to this regimen, all participants in the trial received 2 weekly doses of IMCgp100 at a dose level below the identified weekly recommended Phase II dose (RP2D-QW) and then a dose escalation commenced at the third weekly dose at C1D15. The Phase I testing of the intra-patient escalation dosing regimen is designed to achieve a higher exposure and maximal plasma concentration of IMCgp100 after doses at Cycle 1 Day 15 (C1D15) and thereafter.

Detailed description:
This is a Phase I/II clinical study of IMCgp100 in participants with advanced uveal melanoma.

This is a Phase I/II study of IMCgp100 administered on a weekly basis with an intra-patient escalation dosing regimen. The intra-patient escalation occurred at the third weekly dose on Cycle 1 Day 15 (C1D15). According to this regimen, all participants in the trial received 2 weekly doses of IMCgp100 at a dose level below the identified weekly recommended Phase II dose (RP2D-QW), and then a dose escalation commenced at the third weekly dose at C1D15 with the goal to achieve a long-term dosing regimen at a dose higher than that identified for the weekly dosing regimen (RP2D-QW). The dose escalation identified the intra-patient escalation regimen (RP2D-IE).

The Phase I portion of the study was a standard 3+3 dose escalation design.The recommended Phase II dose of the intra-patient escalation dose regimen (RP2D-IE) was identified and expansion cohorts in metastatic uveal melanoma was accrued based on prior therapy.

Arms:
arm 1: Dose escalation cohorts of the intra-patient escalation regimen. arm 2: Dose expansion cohort with the recommended phase 2 dose of the intra-patient dose escalation regimen.

Interventions: intervention 1: IMCgp100
Intervention descriptions: intervention 1: Bispecific soluble HLA-A2 restricted gp100-specific T-cell receptor fused to anti-CD3

Protocol document:
Prot_000.pdf: 
PROTOCOL NUMBER:  IMCgp100-102 
Investigational Product:  IMCgp100 
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CONFIDENTIAL AND PROPRIETARY 
Clinical Study Protocol IMCgp100-102 
A Phase 1/2, Open-label, Multi-center Study of the Safety and Efficacy of 
IMCgp100 using the Intra-patient Escalation Dosing Regimen in Patients 
with Advanced Uveal Melanoma  
Sponsor:  Immunocore, Ltd. 
101 Park Drive, Milton Park 
Abington, OX14 4RY 
United Kingdom  
EUDRACT Number:  2015-004222-34 
IND Number:  114,314 
Development Phase:  1/2 
Sponsor emergency contact:  
 
 
 
Protocol Versions: 
Current:   
v.8.0
Date of finalization:   
26 November 2018
Previous: 
v.7.0 (15 December 2017)
This document contains confidential and proprietary information which is the property of Immunocore Ltd, United 
Kingdom, and therefore is provided in confidence for your review. It is understood that this information will not be 
disclosed to others without written approval from Immunocore Ltd. 
This study will be conducted in compliance with the Declaration of Helsinki (with amendments), and in accordance 
with local legal and regulatory requirements. 
NCT02570308


 
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Protocol Version History 
Version 
Title 
Date 
1.0 
Original Protocol 
 
2.0 
Amendment 1 
08 Dec 2015 
3.0 
Amendment 2 
11 Jan 2016 
4.0 
Amendment 3 
23 May 2016 
5.0 
Amendment 4 
07 Sep 3016 
6.0 
Amendment 5 
11 Apr 2017 
7.0 
Amendment 6 
15 Dec 2017 
7.0 DE 
Local DE 
Amendment 1 
15 May 2018 
8.0 
Amendment 7 
26 November 2018 


 
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Amendment 7 
Amendment Rationale 
This amendment is done to clarify the interim and final analysis that will be done to assess the efficacy of 
IMCgp100 in the Phase 2 expansion phase.  In addition, the amendment clarifies several changes that 
were made in prior amendments including the allowed prior therapies in the expansion phase, 
requirements for hospitalization, and further clarification of imaging assessments, contraceptive 
requirements and the informed consent process.  This amendment incorporates the changes made in the 
local German amendment which updates the contraception requirement for women of child-bearing 
potential to be consistent across IMCgp100 clinical trials and to be consistent with Clinical Trial Facilitation 
Group recommendations.  
Testing of all patients for HIV and hepatitis B and C infections if required by local regulations is added. 
An overall benefit-risk assessment has been added to the protocol rationale. 
Changes to the protocol 
1. 
Clarification of the Interim and Final analyses for the Phase 2 expansion cohort  
(Sections 9.1 & 9.6.1): This amendment specifies the population and timing of the planned 
interim and final analyses. 
2. 
Clarify allowed prior treatments (Sections 3.2, 5.2, 9.1 & 9.6.1):  As defined in the prior 
amendment, the Phase 2 expansion cohort enrolls patients who have received prior therapy 
for metastatic uveal melanoma.  This amendment seeks to clarify the allowable and required 
prior therapies. 
3. 
Clarify the requirements for hospitalization (Section 6.2): As defined in the protocol, patients 
are required to have an overnight, inpatient hospitalization for the first 3 doses of IMCgp100.  
The amendment clarifies that “inpatient hospitalization” refers to a facility with fully 
functional resuscitation facilities, 24 hour monitoring and physician availability. 
4. 
Clarified definition of confirmed irPD per modified irRECIST for patients who continue 
IMCgp100 therapy beyond initial PD per RECISTv1.1 
5. 
Clarify imaging assessments (Sections 4.6): Hepatic MRI in addition to abdominal CT has been 
required to compare MRI and CT scanning in the Phase 1 dose escalation cohorts.  Given the 
expansion of the study and to reduce the burden on patients, the imaging will be refined to 
allow either CT or MRI to be done for tumor assessment and no longer require both 
modalities. 
6. 
Added exploratory objective (Sections 4.3, 4.6, and Table 4-1) to determine best response 
based on investigator assessment for subsequent anti-cancer therapy. 
7. 
Revised secondary endpoint (Protocol Synopsis, Sections 4 and 9.6.1): The secondary 
endpoint to determine the rate and duration of immune responses was added. 
8. 
Addition of biochemical assessments (LDH and CRP) before and after the initial 3 doses to 
explore pharmacodynamic changes after IMCgp100 administration and association with 
response. 


 
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9. 
Optimization of ctDNA collection timepoints and objectives (Section 7.4): Additional time 
points were added for ctDNA collection to assess pharmacodynamic changes after treatment 
as well as to evaluate for predictors of resistance to treatment. 
10. 
Removal of screening window for HLA testing. Because HLA testing is a genetic test and does 
not change with time, the window of 120 days has been removed. 
11. 
Change to exclusion criterion #19 and addition of Section 6.6 on contraception requirements 
(Section 5.3 and Section 6): Contraception requirement for women of child-bearing potential 
was changed to be consistent across IMCgp100 clinical trials and to be consistent with Clinical 
Trial Facilitation Group recommendations. 
12. 
Update of exclusion criteria #7 and #8 to add testing for HIV and Hepatitis B and C as per local 
regulations (Section 5.3):  Screening for HIV and Hepatitis B and C will be done if required by 
local regulations. 
13. 
Addition of Section 2.4 regarding the overall benefit-risk assessment 
14. 
Inclusion of Table 7-3 to clarify frequency of vital signs. 
15. 
Modification of Section 11.3 to harmonize the informed consent procedures with inclusion 
criterion #2 and clarify the informed consent process. 
16. 
Increased duration of safety follow up period (Sections 3.3, 7.2.3, 7.2.5, 8.1, 8.5, 9.1, & 9.6.2.1 
as well as Table 7.1) to provide further safety information and be consistent across IMCgp100 
clinical trials   
17. 
Clerical Changes are made throughout the protocol to improve clarity. 
Institutional Review Board/Independent Ethics Committee 
A copy of this amended protocol will be sent to the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) and Health Authorities. The changes described in this amended protocol require IRB or 
IEC approval. Changes herein affect the Informed Consent, and sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this amended 
protocol. The revised ICF will replace the previous ICF. 
 


 
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7.0 DE Local Amendment 1 
Amendment Rationale 
This amendment updates the contraception requirement for women of child-bearing potential to be 
consistent across IMCgp100 clinical trials and to be consistent with Clinical Trial Facilitation Group 
recommendations.  
Testing of all patients for HIV and hepatitis B and C infections is added if required by local regulations. 
An overall benefit-risk assessment has been added to the protocol rationale. 
Changes to the Protocol 
1. Change to exclusion criterion #19 and addition of Section 6.6 on contraception regulations 
(Section 5.3 and Section 6) 
2. Update of exclusion criteria #7 and #8 to add testing for HIV and hepatitis B and C as per local 
regulations (Section 5.3) 
3. Addition of Section 2.4 regarding the overall benefit-risk assessment 
4. Modification of Section 11.3 to harmonize the informed consent procedures with inclusion 
criterion #2 and clarify the informed consent process. 
 
 


 
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Amendment 6 
Amendment Rationale 
This amendment transitions the dose expansion cohort component of the study, designed to explore the 
recommended Phase 2 dose that was defined in the Phase 1 testing of the intra-patient escalation regimen 
(RP2D-IE, 68 mcg) to more formal Phase 2 testing in patients with metastatic uveal melanoma who are 
treated in the second or third line setting in this trial (Amendment 6, Protocol version 7.0, 15 December 
2017).  
Tumor responses have been observed in the preliminary dose escalation cohorts of this study and these 
responses have been associated with long duration of response as reported recently (Sato, 2017;  
Carvajal, 2017). Based on the observation of durable partial responses and minor responses (defined as a 
tumor response where the sum of the longest diameters [SLD] of target lesions is reduced by 10%–to 29%) 
in the dose escalation cohorts of this study, the dose expansion cohort in the trial is modified to provide 
a formal analysis of the anti-tumor efficacy in this patient population using the objective response rate 
(ORR) by independent review as the primary efficacy endpoint in this portion of the study. Two separate 
expansion cohorts in this study are defined based on prior therapy:   
1. Cohort A:  Patients will have experienced disease progression with 1 systemic treatment 
regimen containing a checkpoint inhibitor, including either a CTLA4 inhibitor (ipilimumab or 
tremelimumab) and/or a PD-1/PD-L1 inhibitor. Any prior liver-directed therapy (LDT) is 
acceptable in this cohort.  
2. Cohort B:  Patients will have experienced disease progression with 1 or 2 prior lines of therapy, 
including up to 1 prior line of LDT. LDT will be considered a line of therapy for enrolling this 
cohort. Prior checkpoint inhibitor therapy is acceptable but not required in this cohort. 
Given the formal efficacy measures implemented in this dose expansion cohort, the study will be 
designated as a Phase 1/2 to reflect this new endpoint.  
The pattern of clinical response to immunotherapeutic agents differs from that observed with cytotoxic 
therapies. There is accumulating evidence that a proportion of patients with advanced melanoma treated 
with immunotherapy agents, including IMCgp100, may develop initial radiographic progression of the 
tumor before demonstrating meaningful clinical benefit. This delayed response to therapy or immune-
mediated tumor flare (pseudo-progression) is followed by prolonged periods of disease stabilization in 
some patients or more rarely, objective tumor responses. To allow patients to continue therapy beyond 
an initial assessment of progressive disease according to RECISTv1.1, this amendment provides additional 
detail delineating criteria for treatment beyond progression (per modified irRECIST). Patients must meet 
specific clinical criteria and provide additional informed consent to continue therapy beyond an initial 
assessment of disease progression. If disease progression is subsequently confirmed per modified 
irRECIST, treatment must be discontinued. 


 
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This amendment removes screening ophthalmologic and audiology assessments. Prior to initiation of the 
IMCgp100 Phase 1 investigation, the eye and ear were identified as potential target organs for toxicity, 
based on expression of the antigen in these target tissues. To date, and across the IMCgp100 development 
program, there have been no clinically significant adverse events involving vision and/or hearing (please 
refer to the most recent IMCgp100 Investigator’s Brochure for details). This amendment removes 
screening ophthalmologic and audiology assessments and retains these assessments in the setting of 
treatment-emergent toxicity. 
 
 
  
Changes to the Protocol 
1. Increased the sample size of the Phase 2 expansion cohorts (from approximately 40 patients to 
approximately 150 patients) and added the primary endpoint of the single-arm Phase 2 expansion 
cohort of ORR assessed by independent central review based on RECISTv1.1  
2. Clarified the criteria for treatment beyond progression and treatment discontinuation in the 
circumstance of treatment beyond progression using modified irRECIST. The rationale for 
treatment beyond progression is provided 
3. 
 
 
4. Removed screening ophthalmologic exam and audiologic assessment 
5. A window for the infusion time is added by extending the acceptable infusion time from 15 
minutes to 15–20 minutes 
6. Added additional guidance for the management of treatment-related toxicity including 
hypotension and cytokine release events (that are generally observed 2–24 hours after the dose 
of IMCgp100), rash, and pruritus 
7. Clarified that anti-tumor response as assessed by immune-related response criteria (irRECIST) is 
an exploratory endpoint 
8. Clarified that an Independent Data Monitoring Committee will review the safety data from the 
Phase 2 expansion cohorts on an ongoing basis and will also review both efficacy and safety after 
approximately 75 patients have been recruited to Cohort B to monitor the benefit-risk profile 
9. Clarified tumor biopsy requirements in the Phase 1and Phase 2 cohorts 
10. Corrected typographical errors and inserted minor clarifications throughout to improve 
readability and content presentation 


 
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Institutional Review Board/Independent Ethics Committee 
A copy of this amended protocol will be sent to the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) and Health Authorities. The changes described in this amended protocol require IRB or 
IEC approval. Changes herein affect the Informed Consent, and sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this amended 
protocol. The revised informed consent form will replace the previous informed consent form. 


 
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Amendment 5 
Amendment Rationale 
This amendment will update the nomenclature of the dose levels and the recommended Phase 2 dose 
(RP2D) of IMCgp100 utilizing the intra-patient escalation (Amendment 5, protocol version 6.0, dated 11 
April 2017). No changes are made in the dose preparation guidance; thus, there is no change in the actual 
doses administered in this study. Recent information described below indicates that the actual doses 
administered and defined in this Phase 1 study are more accurately defined and lower than the original 
protocol-specified dose levels.  
Individual doses of IMCgp100 are prepared from a concentrated, frozen stock solution (0.5 mg/mL) by a 
2-step dilution procedure in the drug preparation guidelines, requiring dilution of approximately 2500-
fold to accurately achieve the microgram (mcg) doses. The dilution procedure is described in the Pharmacy 
Handling Instructions, provided for each dose level administered, e.g., 20 mcg and 30 mcg. The dilution 
procedure utilizes 2 saline infusion bags; the first is the dilution bag (a labelled 50 mL bag) and the second 
is the actual infusion bag (100 mL). 
The protocol-specified doses in this study were intentionally determined before the study began to 
represent the maximum theoretical dose that could be prepared and administered based on the labelled 
fill volumes of the dilution bags (range of 54–64 mL). The Pharmacy Handling Instructions are authored 
using the lowest potential dilution bag volumes as the start volume and thus, the highest initial 
concentrations of IMCgp100 at dilution step 1 to calculate doses. Setting the protocol-specified dose 
based on the maximum theoretical dose ensured that no patients received actual doses with IMCgp100 
quantities above the protocol-specified dose. However, newly available empirical data demonstrate that 
although there is a labelled range of bag volumes (54–64 mL per packaging), there exists a narrow 
distribution of the actual fill volumes at the first dilution step (generally 57–59 mL). Thus, the doses 
actually prepared and administered in this study were accurate and represented a lower point estimate 
than stated in the original protocol.  
Based on the 2-step dilution procedure used to prepare IMCgp100 doses and considering the conservative 
approach to the variance in the fill range for the primary dilution bag, the protocol-specified doses for the 
higher dose cohorts in the IMCgp100-102 trial and the final RP2D were over-estimates of the actual 
administered dose. Based on the available empirical evidence of dilution bag fill volumes (dilution step 1), 
it is important to correct the over-estimate of the actual dose administered (e.g., update to the RP2D from 
75 mcg to 68 mcg). The 68-mcg dose level is the most accurate within the range produced by the dilution 
procedure and is the RP2D in this study. Doses of 75 mcg and 80 mcg have a differential of approximately 
7 mcg based on the actual bag volumes, and doses below 75 mcg have an approximate 6 mcg differential. 
Based on the limited impact at the lower doses (20 mcg and 30 mcg doses) no change in these protocol-
specified doses is warranted.  
As safety data are collected in this study, the management guidance is updated for adverse events, based 
on the collective experience of the principal investigators in this study including updates of the events of 
cytokine release syndrome and hypotension.  


 
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Changes to the Protocol 
1. The protocol-specified doses of IMCgp100 are updated throughout the protocol as described 
above from Cycle 1 Day 15 and beyond for the various dose escalation cohorts. This includes 
updates to the 60 mcg, 70 mcg, 75 mcg, and 80 mcg dose levels 
2. Table 6-2 Dose Level has been updated to reflect the conduct of the dose escalation cohorts and 
updated protocol-specified dose levels 
3. Updated adverse event management guidance is provided, including updated management of the 
events of cytokine release syndrome and hypotension  
4. Updated the instruction that the intravenous bag containing IMCgp100 must be used within 16 
hours of dilution/mixing 
Institutional Review Board/Independent Ethics Committee 
A copy of this amended protocol will be sent to the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) and Health Authorities. The changes described in this amended protocol require IRB or 
IEC approval. Changes herein affect the Informed Consent, and sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this amended 
protocol. The revised informed consent form will replace the previous informed consent form.


 
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Amendment 4   
Amendment Rationale 
 
 
 
 
 
 
, this trial will only enroll patients with expression of the HLA-A*0201 allele determined 
centrally.  
In addition, this amendment will implement several changes principally related to the recommended 
Phase 2 dose intra-patient escalation (RP2D-IE) expansion cohort. Given the encouraging emerging clinical 
safety and efficacy data with IMCgp100 in uveal melanoma (UM) where a strong signal of disease 
stabilization has been observed in early dosing cohorts in this study, the size of the RP2D-IE expansion 
cohort increased from 20 to 40 patients. This increase in sample size will provide a larger safety dataset 
and more robust point estimate of overall survival in the selected patient population. This cohort will 
enroll a second line population following disease progression a checkpoint inhibitor, including inhibitors 
of CTLA-4, PD-1, and PD-L1 to assess the safety and efficacy of IMCgp100 following prior immunotherapy 
to inform future development in this setting. An independent central review of imaging assessments will 
be performed in this Phase 2 dose expansion cohort. As a substantial majority of patients with metastatic 
UM harbor hepatic metastases, and these metastatic lesions can be difficult to assess even with current 
high resolution imaging techniques, the central review is designed to assess the utility of computed 
tomography versus magnetic resonance imaging in imaging of hepatic metastases and provide cross-
validation of the investigator-reported tumor responses.  
Finally, further translational work is incorporated into the Phase 2 RP2D-IE cohort in this study. The 
landscape of somatic genetic mutations in UM differs significantly from cutaneous melanoma. Analysis of 
circulating tumor DNA is an emerging platform technology that detects tumor-derived somatic mutations 
from the peripheral blood on an individual patient and allows for longitudinal evaluation of these 
mutations during the course of treatment. Early response markers of mutation load in the circulation will 
be studied in the RP2D-IE expansion cohort. These markers will be studied to determine if either specific 
somatic mutations present at Baseline or if early changes in mutation load in the peripheral circulation is 
predictive of patients with favorable response to IMCgp100.  


 
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Changes to the Protocol 
1. Increased the sample size (Section 9.9) and changed the inclusion criteria (Section 5.2) for the 
RP2D-IE expansion cohort to include approximately 40 patients treated in the second-line setting 
following disease progression with a checkpoint inhibitor 
2. Changed inclusion criteria (Section 5.2) to require central testing for the HLA-A*0201 allele 
expression and increased the pre-screening window for HLA assessments to 60 days 
3. Reduced the number of electrocardiogram and pharmacokinetic assessments to be performed in 
patients enrolled in the RP2D-IE expansion cohort (Section 7.3, Tables 7-5 and 7-6, respectively) 
4. Added description of central review of imaging data (Section 7.3.1.1) 
5. 
 
 
 
6. Added additional guidance for the management of treatment related toxicity including updated 
guidance for infusion-related reactions (that are generally observed 2–24 hours after the dose of 
IMCgp100) and added guidance regarding hepatic function abnormalities (Section 6.8, Table 6-6) 
7. Corrected a discrepancy in the Statistical Methods section to clarify that overall survival is a 
secondary study endpoint 
8. Corrected typographical errors and inserted minor clarifications throughout to improve 
readability and content presentation 
Institutional Review Board/Independent Ethics Committee 
A copy of this amended protocol will be sent to the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) and Health Authorities. The changes described in this amended protocol require IRB or 
IEC approval. Changes herein affect the Informed Consent, and sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this amended 
protocol. The revised informed consent form will replace the previous informed consent form.


 
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Amendment 3  
Amendment Rationale 
This amendment will implement a change in the definition of dose limiting toxicity (DLT) with respect to 
the recent observations of transient elevations of hepatic transaminases, alanine aminotransferase (ALT), 
and aspartate aminotransferase (AST), in patients with uveal melanoma (UM) in the 2 ongoing Phase 1 
trials with IMCgp100, the first-in-human (FIH) study (IMCgp100-01) and this UM Phase 1 study 
(Amendment dated 23 May 2016). In these 2 studies, 3 patients with UM and hepatic metastases 
experienced transient grade 2 (n=2) and grade 3 (n=1) elevations of ALT and AST at the first dose of 
IMCgp100 that resolved within days of dosing and did not recur with rechallenge. In each of the 3 patients 
with grade 2–3 elevations, the next dose was not delayed due to the liver function test (LFT) changes. In 
addition, 1 patient with extensive hepatic metastases treated in the FIH study experienced a grade 4 
elevation of hepatic transaminases with the first dose that resolved over a longer time course than the 3 
transient grade 2 and 3 elevations discussed above. This patient with the grade 4 LFT elevations was 
rechallenged with a second dose of IMCgp100 with no recurrence of LFT elevations. Based on the 
observation of multiple patients with UM and hepatic metastases with transient and non-dose limiting 
elevations of ALT and/or AST, the DLT criterion for elevations in ALT and AST has been modified to exclude 
patients with transient grade 3 elevations in ALT and/or AST that are associated with normal bilirubin and 
where the elevated ALT and/or AST resolves to grade 1 or lower within 72 hours. Grade 4 elevations in 
ALT and/or AST, regardless of time course, will remain as DLTs.  
In this Phase 1 study (IMCgp100-102), 1 patient with a history of adrenal insufficiency developed 
hypotension approximately 24 hours following the sixth dose of IMCgp100. Based on the observation of 
the immune-related infusion toxicity in patients with UM, combined with the increased risk for 
hypotension in patients with adrenal insufficiency due to an inability to mount a stress cortisol response 
in the setting of treatment with IMCgp100, this amendment will now exclude all patients with adrenal 
insufficiency. Similarly, patients receiving chronic corticosteroid therapy for any reason are also excluded 
due to the potential dysfunction of the hypothalamic-pituitary-adrenal axis in mediating response to 
stress.  
Changes to the Protocol 
 
Implemented new DLT criterion for transient grade 3 ALT and/or AST elevations to be excluded 
from DLT provided these events are not associated with change in bilirubin and resolve to grade 
1 or lower within 72 hours 
 
Changed exclusion criterion number 14 to exclude any patient with a history of adrenal 
insufficiency or any patient requiring long-term corticosteroid treatment  
 
The definition of lost to follow up is clarified in Section 7.2.6 
 
Corrected typographical errors and inserted minor clarifications throughout to improve 
readability and content presentation 


 
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Institutional Review Board/Independent Ethics Committee 
A copy of this amended protocol will be sent to the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) and Health Authorities. The changes described in this amended protocol require IRB or 
IEC approval. Changes herein affect the Informed Consent, and sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this amended 
protocol. The revised informed consent form will replace the previous informed consent form.


 
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Amendment 2  
Amendment Rationale 
This amendment will implement monitoring changes for the event of hypotension in the intra-patient 
dose escalation regimen (Amendment dated 12 January 2016). These monitoring changes are in response 
to infusion related toxicity with associated hypotension that has been observed in the ongoing first-in-
human Phase 1 study of IMCgp100 in metastatic melanoma (study number IMCgp100-01).  
Patients with the diagnosis of uveal melanoma have been treated with IMCgp100 in the recommended 
Phase 2 dose expansion cohort in the Phase 1 study (IMCgp100-01) and have experienced infusion-related 
toxicity at Cycle 1 Day 1 (C1D1) or Cycle 1 Day 8 (C1D8), including pyrexia, facial edema, and hypotension. 
Based on review of the clinical cases of hypotension, additional monitoring procedures are implemented 
here to screen all patients for risk of hypotension during the intra-patient dose escalation.  
Updates have been made to the monitoring for patients during the first weeks of dosing with IMCgp100. 
Patients will be monitored overnight as an in-patient for each of the first 3 doses of IMCgp100 during the 
intra-patient escalation at C1D1, C1D8, and C1D15. In-patient observation for C1D22 will be mandatory if 
the patient experienced infusion toxicity involving NCI CTCAE grade 2 or greater hypotension requiring 
medical intervention at the previous dose on C1D15.  
Changes to the Protocol 
1. Implemented new monitoring strategy for occurrence of hypotension in the study. Mandatory 
hospitalization for the C1D8 dose is implemented. This hospitalization is in addition to the 
previous mandatory inpatient observations for the C1D1 and C1D15 doses. (Section 6.2 and 
Section 7.3.4)  
2. Guidance for inpatient monitoring for the C1D22 dose are provided and based upon the individual 
patient’s tolerability of the first 3 doses (C1D1, C1D8, and C1D15; Section 6.2) 
3. Revised safety data for IMCgp100-01 study to the current Investigator’s Brochure (Ed 7, issued 17 
December 2015) and to reflect recent infusion-related toxicity events of grade 2 or greater 
hypotension 
4. Revised exclusion criteria to reflect the appropriate methods of highly effective contraception 
5. Corrected typographical errors and inserted minor clarifications throughout to improve 
readability and content presentation 
Institutional Review Board/Independent Ethics Committee 
A copy of this amended protocol will be sent to the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) and Health Authorities. The changes described in this amended protocol require IRB or 
IEC approval. Changes herein affect the Informed Consent, and sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this amended 
protocol. The revised informed consent form will replace the previous informed consent form. 


 
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Amendment 1 
Amendment Rationale 
This amendment will implement dosing changes in the intra-patient dose escalation regimen 
(Amendment 1, protocol version 2.0, dated 08 December 2015). These dosing changes are in response to 
infusion-related toxicity with associated hypotension that has been observed in the ongoing first-in-
human Phase 1 study of IMCgp100 in metastatic melanoma (study number IMCgp100-01).  
Patients with the diagnosis of uveal melanoma (UM) have been treated with IMCgp100 in the 
recommended Phase 2 dose expansion cohort in the Phase 1 study (IMCgp100-01) and have experienced 
infusion-related toxicity at Cycle 1 Day 1 (C1D1) or Cycle 1 Day 8 (C1D8), including pyrexia, facial edema, 
and hypotension. Based on these observations in the Phase 1 study, and considering that (1) UM is defined 
with a higher expression of the antigen (gp100), and (2) the preclinical observation (described in the 
protocol below) of potentially enhanced sensitivity of UM cells to IMCgp100, the doses in this Phase 1 
study in the first 2 weeks will be reduced further in all patients in this study.  
The first doses administered as part of this intra-patient escalation regimen at C1D1 and C1D8 in this 
dosing regimen will be reduced from the previous dose of 40 mcg to 20 mcg (at C1D1) and 30 mcg (at 
C1D8) in all patients treated as part of this study to mitigate the potential for infusion toxicity associated 
with hypotension. Dose escalation will then proceed at C1D15 as planned.  
Changes to the Protocol 
1. Implemented dosing changes in the intra-patient dose escalation regimen with reduction of 
the starting dose on C1D1 to 20 mcg and C1D8 to 30 mcg 
2. Added large disease burden in the liver as an exclusion criterion in the dose escalation portion 
of the study (patients with replacement of > 60% of the liver with disease are excluded), due 
to the possibility of hepatic toxicity 
3. Sponsor emergency contact information has been updated 
4. Added an immunogenicity sample at C1D8 
5. Corrected typographical errors and inserted minor clarifications throughout to improve 
readability and content presentation 
Institutional Review Board/Independent Ethics Committee 
A copy of this amended protocol will be sent to the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) and Health Authorities. The changes described in this amended protocol require IRB or 
IEC approval. Changes herein affect the Informed Consent, and sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this amended 
protocol. The revised informed consent form will replace the previous informed consent form.


 
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Table of Contents 
Protocol Version History ............................................................................................................................... 2 
Amendment 7 ............................................................................................................................................... 3 
Amendment Rationale ............................................................................................................................. 3 
7.0 DE Local Amendment 1 ...................................................................................................................... 5 
Amendment 6 ............................................................................................................................................... 6 
Amendment 5 ............................................................................................................................................... 9 
Amendment 4 ............................................................................................................................................. 11 
Amendment 3 ............................................................................................................................................. 13 
Amendment 2 ............................................................................................................................................. 15 
Amendment 1 ............................................................................................................................................. 16 
Table of Contents ........................................................................................................................................ 17 
List of In-text Tables .................................................................................................................................... 23 
List of In-text Figures ................................................................................................................................... 24 
Protocol Signatures ..................................................................................................................................... 25 
Protocol Synopsis ........................................................................................................................................ 27 
List of Abbreviations ................................................................................................................................... 35 
1 
Background......................................................................................................................................... 38 
1.1 
Overview of Disease Setting ....................................................................................................... 38 
1.2 
Overview of IMCgp100 ............................................................................................................... 39 
1.3 
Non-clinical Experience with IMCgp100 ..................................................................................... 40 
1.3.1 
Preclinical Pharmacology Summary .................................................................................... 40 
1.3.2 
Non-clinical Toxicology Summary ....................................................................................... 41 
1.4 
Clinical Program and Safety Summary ........................................................................................ 42 
1.4.1 
Weekly Dosing:  Dose Escalation Results ............................................................................ 42 
1.4.2 
Weekly Dosing:  RP2D-QW Cohort Results ......................................................................... 44 
1.4.3 
Daily Dosing:  Dose Escalation Results ................................................................................ 45 
1.4.4 
Preliminary Pharmacokinetic Data from First-in-Human IMCgp100-01 Study ................... 45 
2 
Rationale ............................................................................................................................................ 47 


 
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2.1 
Study Rationale and Purpose ...................................................................................................... 47 
2.1.1 
Suppressive Tumor Microenvironment in Uveal Melanoma .............................................. 47 
2.2 
Rationale for Study Design .......................................................................................................... 48 
2.3 
Rationale for Dose and Regimen Selection ................................................................................. 48 
2.3.1 
Rationale for Dose Level Updates ....................................................................................... 50 
2.3.2 
Rationale for Definition of Recommended Phase 2 Dose in the Intra-patient Escalation
 
Regimen .............................................................................................................................. 51 
2.4 
Overall Benefit-Risk Assessment ................................................................................................. 51 
3 
Study Design ....................................................................................................................................... 52 
3.1 
Description of Study Design and Populations ............................................................................. 52 
3.2 
Patient Population ...................................................................................................................... 53 
3.3 
Definition of Study Periods ......................................................................................................... 54 
3.4 
End of Treatment ........................................................................................................................ 56 
3.5 
Definition of End of Study ........................................................................................................... 56 
3.6 
Early Study Termination .............................................................................................................. 56 
4 
Study Objectives and Endpoints ......................................................................................................... 57 
4.1 
Primary Objective ........................................................................................................................ 57 
4.2 
Secondary Objectives .................................................................................................................. 57 
4.3 
Exploratory Objectives ................................................................................................................ 57 
4.4 
Primary Endpoints ....................................................................................................................... 58 
4.5 
Secondary Endpoints .................................................................................................................. 58 
4.6 
Exploratory Endpoints ................................................................................................................. 58 
5 
Population Selection Criteria.............................................................................................................. 61 
5.1 
Patient Population ...................................................................................................................... 61 
5.2 
Inclusion Criteria ......................................................................................................................... 61 
5.3 
Exclusion Criteria ......................................................................................................................... 62 
6 
Study Treatments and Administration ............................................................................................... 65 
6.1 
Study Treatment ......................................................................................................................... 65 
6.1.1 
IMCgp100 ............................................................................................................................ 65 
6.1.2 
Dispensing, Dose Preparation and Administration ............................................................. 66 


 
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6.2 
Summary of Intra-patient Dose Escalation Treatment Regimen ................................................ 66 
6.3 
Dose Escalation Guidelines ......................................................................................................... 68 
6.3.1 
Dose-limiting Toxicities Observation Period ....................................................................... 68 
6.3.2 
Starting Dose Rationale ....................................................................................................... 68 
6.3.3 
Dose Levels .......................................................................................................................... 68 
6.3.4 
Dose Escalation Guidelines ................................................................................................. 69 
6.4 
Definition of Dose-limiting Toxicities .......................................................................................... 71 
6.5 
Concomitant Therapy ................................................................................................................. 73 
6.5.1 
Permitted Concomitant Therapy ........................................................................................ 73 
6.5.2 
Permitted Concomitant Therapy Requiring Caution .......................................................... 73 
6.5.3 
Prohibited Concomitant Therapy ........................................................................................ 74 
6.6 
Contraception ............................................................................................................................. 74 
6.7 
Patient Numbering and Treatment Assignment ......................................................................... 75 
6.7.1 
Patient Numbering .............................................................................................................. 75 
6.7.2 
Treatment Assignment and Randomization ....................................................................... 75 
6.8 
Study Drug Packaging/Labelling, Preparation and Dispensation ................................................ 75 
6.8.1 
Study Drug Compliance and Accountability ........................................................................ 75 
6.8.2 
Drug Supply, Storage, and Disposal .................................................................................... 76 
6.9 
Management and Follow-up of Toxicity ..................................................................................... 76 
6.9.1 
Hypotension ........................................................................................................................ 76 
6.9.2 
Cytokine Release Syndrome ................................................................................................ 77 
6.10 
Treatment Discontinuation ......................................................................................................... 84 
6.10.1 
Criteria for Treatment Beyond Initial RECIST v.1.1 Disease Progression ............................ 85 
6.11 
Study Discontinuation ................................................................................................................. 86 
7 
Study Schedule and Assessments ...................................................................................................... 87 
7.1 
Screening Procedures and Assessments ..................................................................................... 87 
7.1.1 
Screening Assessments ....................................................................................................... 92 
7.2 
Treatment, Treatment Discontinuation and Follow-up Phases .................................................. 93 
7.2.1 
Treatment Period ................................................................................................................ 93 
7.2.2 
Discontinuation of Study Treatment and End of Treatment Visit ...................................... 93 


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7.2.3 
90-day Safety Follow-up Period .......................................................................................... 94 
7.2.4 
Disease Progression Follow-up Period ................................................................................ 94 
7.2.5 
Survival Follow-up Period ................................................................................................... 94 
7.2.6 
Lost to Follow Up ................................................................................................................ 95 
7.3 
Details of All Assessment Types .................................................................................................. 95 
7.3.1 
Efficacy Assessments ........................................................................................................... 95 
7.3.2 
Safety and Tolerability Assessments ................................................................................... 97 
7.3.3 
Physical Examination ........................................................................................................... 97 
7.3.4 
Vital Signs ............................................................................................................................ 97 
7.3.5 
Height and Weight .............................................................................................................. 98 
7.3.6 
Eastern Cooperative Oncology Group Performance Status ................................................ 99 
7.3.7 
Laboratory Evaluations ....................................................................................................... 99 
7.3.8 
Pharmacokinetics and Immunogenicity Assessments ...................................................... 102 
7.3.9 
 ............................................................................................. 104 
7.4 
 ..................................................................................................................... 104 
7.4.1 
 ....................................................................................... 104 
7.4.2 
................... 105 
7.4.3 
 ........................................................................................... 107 
8 
Adverse Events and Safety Reporting .............................................................................................. 110 
8.1 
Assessment of Safety ................................................................................................................ 110 
8.1.1 
Definitions ......................................................................................................................... 110 
8.2 
Criteria for Expectedness .......................................................................................................... 111 
8.3 
Assessment of Causality ............................................................................................................ 111 
8.3.1 
Causality Assessment Required for all Adverse Events .................................................... 111 
8.4 
Adverse Event Reporting .......................................................................................................... 112 
8.4.1 
Expedited Reporting ......................................................................................................... 112 
8.4.2 
Standards for Expedited Reporting ................................................................................... 112 
8.4.3 
Reporting of Out-of-range Laboratory Test Results as Adverse Events ............................ 113 
8.4.4 
Reporting Guidelines for Other Observations .................................................................. 113 
8.4.5 
Pregnancy Reporting ......................................................................................................... 114 


 
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8.5 
Investigator’s Responsibilities ................................................................................................... 114 
8.6 
Sponsor and Clinical Research Organization’s Responsibilities ................................................ 115 
9 
Statistical Methods and Data Analyses ............................................................................................ 116 
9.1 
General Principles ..................................................................................................................... 116 
9.2 
Analysis Sets .............................................................................................................................. 116 
9.2.1 
Full Analysis Set ................................................................................................................. 116 
9.2.2 
Safety Analysis Set ............................................................................................................ 117 
9.2.3 
Per-protocol Analysis Set .................................................................................................. 117 
9.3 
Patient Demographics and Other Baseline Characteristics ...................................................... 117 
9.4 
Treatment Data ......................................................................................................................... 117 
9.5 
Primary Analysis ........................................................................................................................ 117 
9.5.1 
Variables ............................................................................................................................ 117 
9.6 
Secondary Analyses ................................................................................................................... 118 
9.6.1 
Efficacy .............................................................................................................................. 118 
9.6.2 
Safety Objectives ............................................................................................................... 119 
9.7 
Exploratory Analyses ................................................................................................................. 121 
9.7.1 
 ........................................................................................................................ 121 
9.8 
Interim Analysis ......................................................................................................................... 122 
9.9 
Independent Data Monitoring Committee ............................................................................... 122 
9.10 
Sample Size Calculation ............................................................................................................ 123 
9.10.1 
Phase 1 Dose Escalation Cohorts ...................................................................................... 123 
9.10.2 
Phase 2 Dose Expansion Cohorts ...................................................................................... 123 
10 
Data Handling and Management ..................................................................................................... 124 
10.1 
Data Confidentiality .................................................................................................................. 124 
10.2 
Site Monitoring ......................................................................................................................... 124 
10.3 
Data Collection .......................................................................................................................... 124 
10.4 
Database Management ............................................................................................................. 125 
11 
Ethical Considerations and Administrative Procedures ................................................................... 126 
11.1 
Regulatory and Ethical Compliance .......................................................................................... 126 


 
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11.2 
Responsibilities of the Investigator and Institutional Review Board/Independent Ethics 
 
Committee/Research Ethics Board ........................................................................................... 126 
11.3 
Informed Consent Procedures .................................................................................................. 126 
11.4 
Discontinuation of the Study .................................................................................................... 127 
11.5 
Publication of Study Protocol and Results ................................................................................ 127 
11.6 
Study Documentation, Record Keeping, and Retention of Documents ................................... 127 
11.7 
Confidentiality of Study Documents and Patient Records ........................................................ 127 
11.8 
Audits and Inspections .............................................................................................................. 127 
11.9 
Financial Disclosures ................................................................................................................. 128 
12 
References ........................................................................................................................................ 129 
13 
Appendices ....................................................................................................................................... 132 
13.1 
Appendix 1:  Guidelines for Modified RECISTv.1.1 Criteria ...................................................... 132 
13.1.1 
Efficacy Assessments ......................................................................................................... 132 
13.1.2 
Definitions of Measurable and Non-measurable Disease ................................................ 132 
13.1.3 
Methods of Tumor Measurement .................................................................................... 133 
Other Tumor Response Considerations ........................................................................................... 133 
13.1.4 
Definitions of Target and Non-target Lesions ................................................................... 133 
13.1.5 
Determination of Target Lesion Response ........................................................................ 134 
13.1.6 
Determination of Non-target Lesion Response ................................................................ 135 
13.1.7 
Evaluation of Overall Lesion Response ............................................................................. 136 
13.2 
Appendix 2:  Modified Immune-related RECIST Comparison to RECIST v.1.1 .......................... 137 
13.2.1 
Key Changes from RECIST v.1.1 to Modified irRECIST Criteria .......................................... 137 


 
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List of In-text Tables 
Table 1-1 
Summary of IMCgp100 Study ............................................................................... 45 
Table 4-1 
Objectives and Related Endpoints ........................................................................ 59 
Table 6-1 
Dose and Treatment Schedule .............................................................................. 65 
Table 6-2 
Dose Levels in Phase 1 of Intra-patient Escalation Regimen ............................... 69 
Table 6-3 
Criteria for Defining Dose Limiting Toxicities ......................................................... 72 
Table 6-4 
Cytokine Release Syndrome Grading Scalea ....................................................... 77 
Table 6-5 
Recommended Management and Dose Modifications of IMCgp100 by Toxicity
 
Grade for Study Medications ................................................................................. 78 
Table 7-1 
Schedule of Study Assessments ........................................................................... 88 
Table 7-2 
Disease Assessment Collection Plan .................................................................... 96 
Table 7-3 
Post Dose Vital Signs Monitoring .......................................................................... 98 
Table 7-4 
Eastern Cooperative Oncology Group Performance Status .................................. 99 
Table 7-5 
Local Clinical Laboratory Parameters Collection Plan......................................... 100 
Table 7-6 
12-lead Electrocardiogram Collection Plan‡ ........................................................ 101 
Table 7-7 
Pharmacokinetic Assessments ........................................................................... 103 
Table 7-8 
 ...................................................................... 105 
Table 9-1 
Pharmacokinetic Parameters to be Analyzed ..................................................... 121 
Table 13-1 
Response Criteria for Target Lesions .................................................................. 134 
Table 13-2 
Response Criteria for Non-target Lesions ........................................................... 135 
Table 13-3 
Overall Lesion Response at Each Assessment .................................................. 136 
 


 
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List of In-text Figures 
Figure 1-1  
IMCgp100 Structure .............................................................................................. 40 
  
  
  
 ......................................................................................................... 41 
Figure 3-1  
Intra-patient Escalation Regimen .......................................................................... 52 
Figure 3-2  
Study Design ......................................................................................................... 53 
 


IMMUNOCORE 
Protocol Signatures 
Sponsor Signature 
PROTOCOL NUMBER: INICgp"ICJ0-1U2 
lnvestigational Product: 11\/lCgp 100 
I have read the amended protocol and confirm that the protocol follows the current Good Clinical Practice 
guidelines. 
Approved By: 
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PROTOCOL NUMBER:  IMCgp100-102 
Investigational Product:  IMCgp100 
 
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Principal Investigator Signature 
 
I, the undersigned, have reviewed the amended protocol, including the appendices, and I will conduct the 
clinical study as described and will adhere to the tripartite International Conference on Harmonisation 
(ICH) guideline E6 (R2):  Guideline for Clinical Practice (GCP) and all the ethical and regulatory 
considerations stated.  
 
 
 
Signed By: 
 
 
 
 
_______________________________________________       _______________________________ 
Principal Investigator 
 
 
 
 
Date  
 
 
 
_______________________________________________    
Print Name 
 
 
 
_______________________________________________      
Institution Name 
 


 
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Protocol Synopsis 
Study Number 
IMCgp100-102 
Title  
A Phase 1/2, Open-label, Multi-center Study of the Safety and Efficacy 
of IMCgp100 using the Intra-patient Escalation Dosing Regimen in 
Patients with Advanced Uveal Melanoma 
Brief Title 
Phase 1/2 Study of the Intra-patient Escalation Dosing Regimen 
Sponsor and  
Clinical Phase 
Immunocore, Ltd. 
Phase 1/2 
Investigational Agents 
IMCgp100  
Study Type 
Interventional 
Study Purpose and 
Rationale  
IMCgp100-102 is a Phase 1/2 study of the weekly (QW) intra-patient 
escalation dose regimen with IMCgp100 as a single agent in patients 
with metastatic uveal melanoma (mUM). The Phase 1 testing of this 
regimen will aim to achieve a higher exposure and maximal plasma 
concentration of IMCgp100 after doses at Cycle 1 Day 15 (C1D15) and 
thereafter than the exposures achievable at the recommended Phase 2 
dose (RP2D) of the fixed QW dose of 50 mcg (RP2D-QW) without 
additional toxicity. Phase 1 testing will follow the standard 3+3 design 
with dose-limiting toxicity (DLT) as the endpoint and identification of the 
maximum tolerated dose (MTD) and/or the RP2D for the intra-patient 
escalation regimen (RP2D-IE). 
In the Phase 1 first-in-human (FIH) study of IMCgp100 in advanced 
melanoma, a dose escalation was conducted with IMCgp100 
administered on a QW basis. Results of this study have been presented 
(Middleton, 2015).  In this study, the MTD when IMCgp100 is 
administered on a QW basis was determined to be 600 ng/kg. With a 
data cut off of 18 August 2015, it was observed that DLT of grade 3 (n=3) 
and 4 (n=1) hypotension in the QW dosing cohort was observed with the 
first or second dose in this trial. Based on observed safety and the 
pharmacokinetic (PK) profile a flat dosing regimen was implemented 
across the program and the RP2D of the weekly schedule (RP2D-QW) 
was identified as 50 mcg QW. This dose and regimen have been adjusted 
based on emerging safety in the trial and dosing adjustments were 
implemented in the FIH QW dosing expansion cohort (IMCgp100-01, 
NCT01211262).  


 
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In this same FIH study, several patients with mUM were treated in the 
QW dosing regimen at the MTD dose level (600 ng/kg) and at the dose 
level above MTD, 900 ng/kg (n=5, data cut off 18 August 2015). Based 
on review of the observed objective responses in the Phase 1 trial in 
uveal melanoma (UM) as well as objective responses noted in cutaneous 
melanoma, it was noted that patients with larger diameters of disease 
burden (both cutaneous and UM) experienced objective tumor 
responses at the higher overall exposures to IMCgp100.  
The current study of the intra-patient dose escalation regimen is based 
on 2 observations in the clinic:  (1) objective partial and minor tumor 
responses in patients with higher tumor burdens were generally 
observed at the higher absolute doses in the Phase 1 trial, and (2) the 
occurrences of more severe toxicity leading to dose limitation were 
limited to the first 2 weeks of dosing on C1D1 and C1D8. Based on these 
2 observations, it is hypothesized that an increased exposure to drug in 
the weeks following the occurrence of the more severe toxicity (at the 
first 2 doses) may lead to an enhanced tumor response in a setting of an 
unfavorable tumor microenvironment such as UM. 
Primary Objectives 
Phase 1 Dose Escalation:  The primary objective is to identify the MTD 
and/or the RP2D of IMCgp100 in the intra-patient dose escalation 
regimen (RP2D-IE). 
Phase 2 Dose Expansion:  The primary objective is to estimate the 
objective response rate by independent central review (ICR) based on 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1) in 
patients with advanced UM who are treated with the RP2D-IE of 
IMCgp100.  
Secondary Objectives 
 
To characterize the safety and tolerability of IMCgp100 in the intra-
patient dose escalation regimen 
 
To characterize the PK profile of single-agent IMCgp100 in the intra-
patient dose escalation regimen 
 
To assess the anti-tumor efficacy of IMCgp100 with the parameters 
of objective response rate (Phase 1), overall survival, progression-
free survival (PFS), disease control rate (DCR), time to response, and 
the duration of response (DOR).   
 
To evaluate the incidence of anti-IMCgp100 antibody formation 
following multiple infusions of IMCgp100 in the intra-patient dose 
escalation regimen 
 
To determine the rate and duration of minor responses (defined as 
tumor response with a reduction in the sum of longest diameters of 


 
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10%–29%) and immune responses (as assessed by area under the 
tumor response curves [AUC]) 
Study Design 
This is a Phase I12 study of IMCgp100 administered on a QW basis with 
an intra-patient escalation dosing regimen. The intra-patient escalation 
occurs at the third QW dose on C1D15. According to this regimen, all 
patients in the trial will receive 2 QW doses of IMCgp100 at a dose level 
below the identified RP2D-QW, and then a dose escalation will 
commence at the third QW dose at C1D15 with the goal to achieve a 
long-term dosing regimen at a dose higher than that identified for the 
RP2D-QW. In this dosing regimen, each patient will undergo a fixed 
intra-patient dose escalation (fixed dosing of 20 mcg at C1D1 and 30 
mcg at C1D8), followed by the dose escalation beginning at C1D15. 
Patients will continue to receive the same escalated dose from C1D15 
and thereafter. The dose escalation will identify the RP2D-IE. 
The Phase 1 portion of the study will be a standard 3+3 dose escalation 
design. After the dose escalation portion is complete and the MTD or 
the RP2D-IE is identified, the Phase 2 expansion cohorts in mUM will be 
enrolled. These two cohorts will enroll patients with mUM and will 
enroll approximately 150 patients combined.  
 
Cohort A will enroll patients with mUM in the second-line 
setting after disease progression following systemic treatment 
with a checkpoint inhibitor with any prior liver directed therapy 
(LDT)  
 
Cohort B will enroll patients with mUM in the second or third-
line setting with up to one prior LDT regimen  
 
Additional details regarding expansion cohorts are outlined in 
Key Inclusion Criteria below, Section 3.2 and Section 5.2.  
Population Under 
Study 
The trial will enroll patients with a diagnosis of advanced mUM, defined 
as histologically confirmed diagnosis of UM and metastatic stage IV 
disease at study entry. In the Phase 1 dose escalation portion of the trial, 
patients are eligible with any prior therapy including systemic 
treatments or LDT with an Eastern Cooperative Oncology Group (ECOG) 
performance score of 0 or 1 and meeting all additional eligibility criteria. 
Once the dose is identified in the Phase 1 dose escalation, 2 Phase 2 
expansion cohorts will be enrolled in 2 patient populations:   
1. Cohort A:  Patients will have experienced disease progression 
with 1 systemic treatment regimen containing a checkpoint 
inhibitor, including either a CTLA4 inhibitor (ipilimumab or 


 
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tremelimumab) and/or a PD-1/PD-L1 inhibitor. Any prior LDT is 
acceptable in this cohort.  
2. Cohort B will enroll patients with mUM in the second or third-
line setting with up to one prior LDT regimen.  
Additional details regarding expansion cohorts are outlined in 
Key Inclusion Criteria below, Section 3.2 and Section 5.2 
These Phase 2 expansion cohorts are designed to further characterize 
the safety, tolerability, and preliminary PK and anti-tumor activity of 
IMCgp100. 
Key Inclusion Criteria 
1. Male or female patients age ≥ 18 years of age at the time of 
informed consent 
2. Ability to provide and understand written informed consent prior to 
any study procedures  
3. Histologically or cytologically confirmed diagnosis of mUM 
4. Surgically sterile patients or patients of child-bearing potential who 
agree to use highly effective methods of contraception during study 
dosing and for 6 months after last dose of study drug 
5. Life expectancy of > 3 months as estimated by the investigator 
6. Human leukocyte antigen-A*0201 positive by central assay 
7. ECOG Performance Status of 0 or 1 at Screening 
8. Patients must have disease (measurable or non-measurable 
acceptable) according to RECIST v.1.1 criteria in the Phase 1 dose 
escalation cohorts. Patients must have measurable disease in the 
Phase 2 dose expansion cohorts 
9. Phase 1 dose escalation cohorts only:  any prior therapy is 
acceptable 
10. Phase 2 dose expansion cohorts:   
 
Cohort A:  Patients will have experienced disease progression 
with 1 systemic treatment regimen containing a checkpoint 
inhibitor, including either a CTLA4 inhibitor (ipilimumab or 
tremelimumab) and/or a PD-1/PD-L1 inhibitor. Any prior LDT is 
acceptable in this cohort 
 
Cohort B:  Patients will have experienced disease progression 
with 1 or 2 prior lines of therapy in the metastatic or advanced 
setting including chemotherapy, immunotherapy or targeted 
therapy. Only a single line of local, LDT including 
chemotherapy, radiotherapy, radiofrequency ablation or 
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modality of treatment that is administered until completion of 
treatment or disease progression. For patients who have 
received prior LDT, this will count as a line of therapy. Prior 
surgical resection of oligometastatic liver disease is allowed 
and is not counted as a line of LDT.A patient may have 
discontinued systemic therapy prior to disease progression if 
the patient experienced a significant adverse reaction that 
required treatment discontinuation, as per Investigator’s 
judgment and applicable labelling. Prior checkpoint inhibitor 
therapy is acceptable but not required in this cohort. 
 
A. This means patients with the following treatments are 
eligible under Cohort B: 
o 1 systemic therapy and 1 LDT 
o 1 – 2 systemic therapies and 0 LDT 
o 0 systemic therapy and 1 LDT 
b. Adjuvant therapies and local therapies for treatment 
of disease outside of the liver do not count towards 
the lines of prior therapy.  
11. All other relevant medical conditions must be well-managed 
and stable, in the opinion of the investigator, for at least 28 
days prior to first administration of study drug 
Key Exclusion Criteria  
1. Presence of symptomatic or untreated central nervous system 
(CNS) metastases, or CNS metastases that require doses of 
corticosteroids within the prior 3 weeks to study Day 1. 
Asymptomatic and adequately treated CNS metastases are not 
exclusionary 
2. History of severe hypersensitivity reactions to other biologic drugs 
or monoclonal antibodies 
3. Patient with any out-of-range laboratory values defined as: 
 
Serum creatinine > 1.5 x upper limit of normal (ULN) and/or 
creatinine clearance (calculated using Cockcroft-Gault formula, 
or measured) < 50 mL/min 
 
Total bilirubin > 1.5 x ULN, except for patients with Gilbert’s 
Syndrome who are excluded if total bilirubin > 3.0 x ULN or 
direct bilirubin > 1.5 x ULN 
 
Alanine aminotransferase (ALT) > 3 x ULN 


 
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 
Aspartate aminotransferase (AST) > 3 x ULN 
 
Absolute neutrophil count < 1.0 x 109/L 
 
Absolute lymphocyte counts: (1) Phase 1 and Phase 2 Expansion 
Cohort A:  Absolute lymphocyte count < 0.5 x 109/L; (2) Phase 2 
Expansion Cohort B:  Absolute lymphocyte count < 1.0 x 109/L   
 
Platelet count < 75 x 109/L 
 
Hemoglobin < 8 g/dL 
 
Potassium, magnesium, corrected calcium or phosphate 
abnormality of National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) > grade 1 
4. Phase 1 dose escalation only:  Presence of high tumor burden, 
defined as liver replacement of > 60% hepatic organ volume with 
tumor 
5. Clinically significant cardiac disease or impaired cardiac function, 
including any of the following: 
 
Clinically significant and/or uncontrolled heart disease such as 
congestive heart failure (New York Heart Association grade ≥ 2), 
uncontrolled hypertension or clinically significant arrhythmia 
currently requiring medical treatment 
 
QTcF > 470 msec on screening electrocardiogram (ECG) or 
congenital long QT syndrome 
 
Acute myocardial infarction or unstable angina pectoris < 6 
months prior to Screening 
6. Patients may not have been included in any prior IMCgp100 trial, 
regardless of assigned treatment cohort 
Efficacy Assessments 
Radiologic assessments should be performed as scheduled every 8 or 12 
weeks using a reference to C1D1 and should NOT follow delays incurred 
in the treatment period. 
Tumor response will be determined according to 2 sets of criteria: 
1. RECIST v.1.1 
2. Modified immune-related response criteria (irRECIST) for 
patients 
who 
continue 
treatment 
beyond 
RECISTv1.1 
progression 
Phase 1:  The local investigator’s assessment will be used for the analysis 
of response according to RECIST v.1.1 for efficacy endpoints of the study 


 
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and modified irRECIST, and for treatment decision making (study 
discontinuation 
due 
to 
progressive 
disease 
[PD] 
as 
per 
RECISTv.1.1/modified irRECIST).  
Phase 2:  For the expansion cohorts only, an independent central review 
(ICR) will be used for the analysis of objective response rate and all other 
tumor-related endpoints based on RECIST v.1.1 and irRECIST. 
Investigator assessment data will be used for treatment decision making 
during the study. 
PFS will be assessed using RECIST v.1.1. Patients experiencing PD per 
RECIST v.1.1 criteria may consent to continue to be treated according to 
irRECIST guidelines until confirmed, unequivocal progression is 
documented via modified irRECIST. Progression based on modified 
irRECIST will be assessed as an exploratory endpoint. 
Imaging per CT or MRI will be performed at baseline and scheduled 
follow-up timepoints- additional details are outlined in Section 7.3.1. 
Safety Assessments 
Safety will be monitored by assessing physical examination, vital signs, 
body height and weight, performance status, hematology, chemistry, 
coagulation, urinalysis, thyroid function, pregnancy, ECG, cytokine 
testing, as well as collecting of the adverse events at every visit.  
Biomarker Assessments 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 


 
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Keywords 
IMCgp100, uveal melanoma, T cell redirection, gp100 


 
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List of Abbreviations 
AE 
Adverse event 
AESI 
Adverse event of special interest 
Akt 
Protein kinase B 
ALT 
Alanine aminotransferase 
anti-CD3 
Anti-cluster of differentiation 3 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
C#D# 
Cycle 1 Day 1; Cycle 8 Day 1; Cycle 15 Day 1; Cycle 2 Day 15 
C1D8 
Cycle 1 Day 8 
CD3 
Cluster of differentiation 3 
Cmax 
Maximum observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
ctDNA 
Circulating tumor deoxyribonucleic acid 
CTL 
Cytotoxic T lymphocyte 
CTLA-4 
Cytotoxic T lymphocyte associated protein-4 
DCR 
Disease control rate 
DETC 
Dose escalation teleconference 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
 
 
 
EOT 
End of treatment 
 
 
FAS 
Full analysis set 


 
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FIH 
First-in-human 
GCP 
Good clinical practice 
GNAQ 
Heterotrimeric G protein alpha subunit q 
GNA11 
Heterotrimeric G protein alpha subunit 11 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
HLA 
Human immunodeficiency virus 
Human leukocyte antigen 
HLA-A2 
Human leukocyte antigen-A2 
HLA-A*0201 
Human leukocyte antigen-A*0201 
HLA-DR 
Human leukocyte antigen-DR 
HRQoL 
Health-related quality of life 
IDMC 
Independent data monitoring committee 
ICH 
International Conference on Harmonization 
ICR 
Independent central review 
IEC 
Independent Ethics Committee 
IFN-γ 
interferon gamma 
IHC 
Immunohistochemistry 
IL-# 
Interleukin-# (e.g., IL-6, IL-10) 
IMCgp100 
77 kDa bi-specific protein 
IRB 
Institutional Review Board 
irPD 
Immune-related progressive disease 
irRC 
Immune-related response criteria 
irRECIST 
Immune-related response criteria in solid tumors 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LDT 
Liver-directed therapy 
LFT 
Liver function test 
MEK 
 Mitogen-activated protein kinase/ Extracellular signal-regulated kinase 
MinR 
Minor response 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mUM 
Metastatic uveal melanoma 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 


 
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ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Progressive disease 
PD-1 
Programmed death-1 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PI3-kinase 
Phosphatidylinositol 3-kinase 
PPS 
Per protocol set 
PR 
Partial response 
QD 
Every day 
QW 
Every week 
REB 
Research ethics board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
RP2D-IE 
Recommended Phase 2 dose — intra-patient escalation 
RP2D-QD 
Recommended Phase 2 dose — daily 
RP2D-QW 
Recommended Phase 2 dose — weekly 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SLD 
Sum of longest diameters 
SUSAR 
Suspected, unexpected, serious adverse reaction 
t1/2 
half-life 
TIL 
Tumor infiltrating lymphocyte 
TMTB 
total measured tumor burden 
ULN 
Upper limit of normal 
UM 
Uveal melanoma 


 
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1 BACKGROUND 
 
Overview of Disease Setting 
Melanoma arises from pigment containing cells (melanocytes) present in the skin, eye, and mucus 
membranes. Melanoma most frequently occurs in the skin; however, ocular melanoma arises from 
pigmented cells in the eye. The primary cause of melanoma is thought to be radiation-induced DNA 
damage from ultraviolet light exposure. Melanoma is the most deadly of skin cancers. Globally, in 2012, 
melanoma occurred in 232,000 people and resulted in 55,000 deaths (Cancer Research UK). Cutaneous 
and uveal melanoma (UM) is more common in men than women. UM is a rare type of melanoma where 
the incidence has ranged from 5.3 to 10.9 cases per million (Singh, 2011). Despite its rare incidence rate 
(representing approximately 3% of melanoma cases, approximately 4,000 cases globally per year), UM is 
the most frequent primary intraocular malignancy of the adult eye (85%) (Patel, 2011; Maio, 2013). UM 
is an extremely malignant neoplasm that affects the vascular layers of the eye (iris, ciliary body, and 
choroid) (Maio, 2013). The majority of UM cases in the United States occur in the Caucasian population 
(Andreoli, 2015). UM is  biologically distinct from cutaneous melanoma with differences in the mutational 
landscape, where BRAF and NRAS mutations dominate the landscape in cutaneous melanoma and 
mutations in G protein coupled receptors, q  polypeptide (GNAQ) and alpha 11 (GNA11), dominate in UM 
(Shoustari, 2014). In addition, the mode of spread of disease is distinct between the 2 disease settings, 
with hematogenous spread of uveal versus lymphatic spread in cutaneous, leading to the different 
patterns of metastatic disease with primary liver metastases in UM, contrasted with visceral, bone, and 
brain metastases predominant in cutaneous melanoma (Dunavoelgyi, 2011; Yu, 2014).  
Local therapy approaches in UM generally rely on radiation and surgical enucleation; however, despite 
adequate local therapy, UM metastases are very common and develop in 50% of patients with the liver 
being the predominant metastatic site (90%) (Carvajal, 2014). UM has also been shown to spread to the 
lungs, bones, and skin (Carvajal, 2014; Maio, 2013). The American Joint Committee on Cancer Tumor-
Node-Metastasis staging system is used for UM (Edge, 2010) and represents 1 aspect of the estimated 
prognosis. Molecular markers such as monosomy 3 are used to guide prognosis and risk of metastasis in 
addition to classic histology such as the presence of spindle versus epithelioid (Campbell, 1998). Once 
patients have developed metastatic disease, the prognosis and outcomes are very poor with a median 
survival of less than 12 months, and for those with liver metastases, the median survival is approximately 
6 months (Singh, 2011). Despite much investigation of metastatic uveal melanoma (mUM) in the clinic, to 
date, no systemic therapy has improved survival and no effective therapy has been achieved (Maio, 2013; 
Carvajal, 2014; Luke, 2013; Zimmer, 2015). 
UM has a poor response to cytotoxic chemotherapy, and radiotherapy and therapies for cutaneous 
melanoma have had little impact in the treatment of UM (e.g., BRAF inhibitors, due to the absence of the 
target mutation in UM; Buder, 2013). UM has been characterized by specific driver mutations in guanine 
nucleotide binding protein (G protein), GNAQ or GNA11 leading to the downstream activation of multiple 
signaling nodes, including mitogen-activated protein kinase/ extracellular signal-regulated kinase (MEK), 
phosphatidylinositol 3-kinase (PI3-kinase)/protein kinase B (Akt), protein kinase C, and Yes-associated 


 
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protein (Shoustari, 2014; Yu, 2014). Treatments for mUM can be divided into (1) liver-directed treatments; 
such as surgical resection, ablation, radiation, hepatic arterial chemoinfusion; and (2) systemic 
treatments; such as chemotherapy (anti-neoplastic drugs used alone or in combinations), immunotherapy 
(interferon, interleukin-2, programmed death-1 (PD-1) inhibition and ipilimumab), anti-angiogenetic 
drugs, and recently the targeted agents such as MEK and Akt inhibitors. The targeted agents are applied 
based on the high percentage of patients’ tumors harboring GNAQ or GNA11 mutations; however, these 
therapies have not been as effective as other targeted agents in the BRAF mutation subset (Buder, 2013).  
Recent evidence suggests that immunotherapy for UM is only marginally more effective than cytotoxic 
therapy, where the estimates of the response rate of dacarbazine are between 0–5%. Response rates with 
ipilimumab in this setting range from 0–8% across multiple studies (Maio, 2013; Luke, 2013; Zimmer, 
2015; Carvajal, 2014). The response to new immunotherapy approaches in the uveal subset is significantly 
diminished compared to that for cutaneous melanoma, possibly due to the low mutational burden of UM 
compared to that of cutaneous melanoma (Furney, 2014). The tumor microenvironment of UM is 
characterized by a uniquely suppressive environment with the presence of M2 macrophages and 
immature myeloid cells along with strong FoxP3 expression and CD8+ T cells (Bronkhorst, 2012). Both 
phenotypes are associated with a distinctly immune suppressive environment and this immune infiltrate 
is associated with monosomy 3 in UM and poor prognosis (Maat, 2008; Bronkhorst, 2011). The 
suppressive environment and lack of activity of checkpoint inhibition suggests that mobilization of 
activated T cells with a tumor-specific focus may have anti-tumor activity in this disease setting. With the 
wide and strong expression of gp100 in UM, the application of a redirected T cell approach to gp100 in 
this setting may have enhanced anti-tumor activity (Van Dinten, 2005). Furthermore, with the 
immunologically privileged site of UM, immunotherapy represents a promising treatment approach for 
this devastating and life-threatening condition (Buder, 2013; Woodman, 2012). 
 
Overview of IMCgp100 
IMCgp100 is a 77 kDa bi-specific protein with targeting and effector moieties which is manufactured in 
Escherichia coli (E coli). The targeting portion of IMCgp100 (the T cell receptor) functions to bind to the 
gp100 antigen as presented by major histocompatibility complex Class I on the surface of melanoma cells. 
The targeted gp100 peptide is presented by a subset of the population that express a specific variant of 
the major histocompatibility complex Class I complex known as human leukocyte antigen-A2 (HLA-A2). 
This variant is carried by approximately 50% of the population in the Western World (Middleton, 2003). 
The effector function (anti-cluster of differentiation 3 [anti-CD3]) works by binding and activating T cells 
via cluster of differentiation 3 (CD3). These T cells can be tumor specific cells which are already resident 
in the tumor (tumor infiltrating lymphocytes [TIL]), but circulating polyclonal T cells may also be activated 
as they traffic through the tumor as part of the normal blood supply. CD4+ and CD8+ T cells are both 
activated by IMCgp100 triggering cytolytic activity associated with release of immune mediators 
potentially resulting in a cascade of anti-tumor immune effector mechanisms. T cell proliferation studies 
on CD8 T cell subtypes have shown that effector memory, central memory, and naïve cells all respond to 
IMCgp100 stimulation as well as CD4+ T cells. Memory T cell activation following exposure to IMCgp100 


 
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Figure 1-1 
 IMCgp100 Structure 
IMCgp100 is a biologic with dual effector and targeting ends. The targeting end is an affinity enhanced soluble T cell 
receptor recognizing the gp100 antigen and the effector end is an anti-CD binding domain.  
 
Non-clinical Experience with IMCgp100 
 Preclinical Pharmacology Summary 
IMCgp100 has been shown to induce the full repertoire of cytotoxic T lymphocyte (CTL) activation events 
in a dose-dependent manner in vitro when combined with target melanoma cells. This activation is 
evident at concentrations as low as 1 picomolar (pM) and activity is maximal at a concentration of 1 
nanomolar (nM) irrespective of whether isolated CD8 or peripheral blood mononuclear cells (PBMC) are 
used as the effector cells. Furthermore, maximal killing effects may require up to a few days exposure 
with cancer cells. The activation of CD4 T cells has also been demonstrated at similar concentrations and 
with similar kinetics. Such activation would be expected to augment the CTL mediated immune response 
through the recruitment of other inflammatory cells.  
Using PBMCs from melanoma patients, IMCgp100 has been shown to augment an already present anti-
tumoral response. Finally, the tumor infiltrating T cells that would be the first line of attack in a clinical 
situation would be expected to be outnumbered by melanoma targets. Thus, it has been shown that a 
single T cell is capable of serial killing in vitro. These data demonstrate that IMCgp100 is a potent tumor-
killing agent. 


 
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 Non-clinical Toxicology Summary 
Both the gp100-specific soluble T cell receptor and the CD3 targeting ends of IMCgp100 have been 
demonstrated to have high specificity for the human HLA-A2-gp100 peptide complex and human CD3. 
Therefore, binding and activation of IMCgp100 cannot be demonstrated in non-human primates, which 
show a relatively high degree of sequence homology to human CD3. In addition, both the T cell receptor 
targeting end and CD3 activation arm do not interact at any level in any other species. Given the 
limitations in binding of IMCgp100 and activation of any T cell subsets in any standard toxicology species, 
there is no relevant toxicology species in which IMCgp100 can be tested. 


 
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Tissue cross-reactivity studies with IMCgp100 and published gp100 immunohistochemistry (IHC) 
demonstrate gp100 expression in human melanocytes, and expression levels have been demonstrated 
directly in the retina, melanocytes, the substantia nigra, and the thymus (Takase, 2005; Wagner, 1997). 
Other tissues that are known to contain melanocytes, but to our knowledge have not been directly tested 
for gp100 expression, include the iris, the inner ear, and the choroid plexus of the brain. 
In the absence of a relevant toxicology species, IMCgp100 was investigated for potential reactivity to 
normal tissues other than target melanoma tissue in vitro. IMCgp100 could redirect T cell activity to 
normal cells that are known to express gp100; however, higher concentrations of IMCgp100 were 
required to elicit an effect in these normal tissue cells indicating that there may be a therapeutic window 
between a dose of drug required to effect melanoma cells and that which may cause potential organ 
specific toxicity. These assays were also used to determine a minimal anticipated biological effect level, 
and the starting dose for the first IMCgp100 dose escalation study. Other assays designed to assess 
unexpected reactivity of both the T cell receptor and the anti-CD3 were entirely negative.  
 
Clinical Program and Safety Summary 
IMCgp100 is being studied in an ongoing first-in-human (FIH), open-label, dose escalation study 
(IMCgp100-01). Patients with advanced melanoma were enrolled into 2 separate dose escalation cohorts:  
(1) a weekly (QW) dosing regimen cohort (Arm 1), and (2) a daily (QD) dose x 4 days repeated every 3 
weeks dosing regimen cohort (Arm 2). The study is designed to identify the maximum tolerated dose 
(MTD) or recommended Phase 2 dose (RP2D) of IMCgp100 in the 2 repeat dosing regimens:  (1) QW dosing 
(the RP2D-QW) and (2) daily dosing x 4 days (the RP2D-QD).  
 Weekly Dosing:  Dose Escalation Results 
The QW dosing regimen dose escalation included dose levels from 5 ng/kg up to 900 ng/kg and the MTD 
for this dosing regimen was identified at 600 ng/kg QW (Middleton, 2015). In the review of the safety and 
pharmacokinetic (PK) data for the QW dosing regimen, the RP2D-QW was initially identified as a flat dose 
of 50 mcg administered intravenously (IV) on a QW basis; 
 
 
 
  
 
 
 
 
 
 
 
 
 
  


 
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Please refer to the most recent version of the IMCgp100 Investigator’s Brochure for further details.  


 
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 Weekly Dosing:  RP2D-QW Cohort Results  
 
 
 
 
. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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 Daily Dosing:  Dose Escalation Results 
 
 
 
 
 
  
For further details refer to the most recent version of the IMCgp100 Investigator’s Brochure. 
 Preliminary Pharmacokinetic Data from First-in-Human IMCgp100-01 Study 
 
 
 
 
 
 
 
 
 
  


 
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For detailed information regarding PK data of IMCgp100, refer to the most recent version of the IMCgp100 
Investigator’s Brochure. 
 


 
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2 RATIONALE 
 
Study Rationale and Purpose 
This is a Phase 1/2 clinical study of IMCgp100 in patients with advanced UM. In the Phase 1 FIH study of 
IMCgp100 in advanced melanoma, a dose escalation was conducted with IMCgp100 administered on a 
QW basis (Middleton, 2015). 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 Suppressive Tumor Microenvironment in Uveal Melanoma 
In general, cutaneous melanoma is thought to be 1 of the more immunogenic tumors with significant 
activity observed with immunotherapy options and the first drug approvals in this space (e.g., ipilimumab 
and nivolumab [Bristol Meyers Squibb] and pembrolizumab [Merck]). In contrast, the biology of UM 
suggests potent immunosuppressive properties, unlike the cutaneous subset with a corresponding lack of 
activity with the checkpoint inhibitors (Maio, 2013; Luke, 2013; Zimmer, 2015). Ironically, T cell infiltration 
in UM is predictive of poor survival. In the preclinical setting, there are 2 main hypotheses to explain the 
immunosuppressive nature of UM and none appears mutually exclusive:  (1) T cell extrinsic 
immunosuppression due to negative myeloid influences with high IL-10, NKT activity with M2 wound 
healing phenotype of macrophages possessing potent immunosuppressive capabilities (Sadegh, 2015; Vu, 
2013); and (2) T lymphocyte intrinsic immunosuppression with enhanced regulatory T cell development 
and indoleamine 2-3 dioxygenase expression by existing T cell responses in the setting of metastases as 
opposed to the primary lesions (Verbik, 1997; Whelchel, 1993; Mougiakokos, 2010; Lagouros, 2009). 
Preclinical studies suggest that the development of melanoma liver metastases is associated with 
upregulation of IL-10 in the liver and an elevated expression of IL-10 receptor on liver natural killer cells. 


 
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This impairment of liver natural killer activity is natural killer T cell-dependent and only occurs in hosts 
with melanoma liver metastases. 
 
Rationale for Study Design 
IMCgp100-102 is a Phase 1/2 study of the QW intra-patient escalation dose regimen with IMCgp100 as a 
single agent in patients with mUM.  The Phase 1 testing of this regimen will aim to achieve a higher 
exposure and Cmax of IMCgp100 after doses at Cycle 1 Day 15 (C1D15) and thereafter than the exposures 
achievable at the RP2D of the fixed 50 mcg RP2D-QW without additional toxicity. Phase 1 testing will 
follow the standard 3+3 design with DLT as the endpoint and identification of the MTD and/or the RP2D 
for the Phase 2 intra-patient escalation regimen (RP2D-IE).  
Once the appropriate dose for Phase 2 is identified (RP2D-IE), the Phase 2 expansion cohorts in UM will 
begin. Cohort A will recruit approximately 20 patients to further characterize the safety, tolerability, PK, 
and anti-tumor response of IMCgp100 in patients following therapy with a checkpoint inhibitor and any 
potential liver-directed therapy (LDT). Cohort B will recruit approximately 130 patients to further 
characterize the safety, tolerability, PK, and anti-tumor response of IMCgp100 in patients who have been 
previously treated with 1 or 2 prior lines of therapy in the metastatic or advanced setting, including 
chemotherapy, immunotherapy or targeted therapy and up to a single line of local, LDT.Prior checkpoint 
inhibitor is acceptable in Cohort B but is not required.  
Additional details on Phase 2 Expansion cohorts are provided in Section 3.2 and Section 5.2. 
These cohorts will provide homogenous populations in which to assess safety and anti-tumor efficacy with 
the goal to inform subsequent development of IMCgp100.  
 
Rationale for Dose and Regimen Selection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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 Rationale for Dose Level Updates 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  


 
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 Rationale for Definition of Recommended Phase 2 Dose in the Intra-patient 
Escalation Regimen 
The dose escalation cohorts of this study have been analyzed and the RP2D-IE (dosed at C1D15 and 
beyond) identified at 68 mcg. The preliminary results of the Phase 1 have been presented (Sato, 2017) 
and are summarized here. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Overall Benefit-Risk Assessment 
A significant degree of unmet need exists in the setting of advanced UM. Compared to standard 
treatments utilized in cutaneous melanoma, no treatments have consistently demonstrated a survival 
benefit in UM clinical studies, including dacarbazine and immunotherapy with checkpoint inhibition (e.g., 
ipilimumab or pembrolizumab). IMCgp100 has an acceptable tolerability profile, with generally mild-to-
moderate toxicity beyond the first 2 doses where manageable immune-based toxicities have been 
observed (Middleton, 2016). The study is designed to minimize potential risks through intensive patient 
monitoring and frequent safety assessments based upon available early phase clinical safety data for 
IMCgp100. The preliminary, robust clinical activity of IMCgp100 in the setting of advanced UM, combined 
with the lack of any therapies demonstrating a survival benefit in this indication supports the further 
development of IMCgp100 in patients with advanced UM. 


 
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3 STUDY DESIGN 
 
Description of Study Design and Populations 
This is a Phase 1/2 study of IMCgp100 administered on a QW basis with an intra-patient escalation dosing 
regimen. The intra-patient escalation occurs at the third weekly dose on C1D15. According to this regimen, 
all patients in the trial will receive 2 QW doses of IMCgp100 at a dose level below the identified RP2D-
QW, and then a dose escalation will commence at the third weekly dose at C1D15 with the goal to achieve 
a long-term dosing regimen at a dose higher than that identified for the straight QW dosing regimen 
(RP2D-QW). The dose escalation will identify the RP2D-IE. (Intra-patient dose escalation regimen 
schematic, see Figure 3-1). 
Phase 1:  Dose Escalation 
 
 
 
 
 
 
 
 
Phase 2:  Expansion 
 
Enrollment into the Phase 1 dose escalation portion has been completed and RP2D-IE was determined to be 
68 mcg. 
Figure 3-1 Intra-patient Escalation Regimen  
In this dosing regimen, at C1D1 and C1D8, patients will all receive single-agent IMCgp100 at a dose  below the 2RP2D-
QW of 50 mcg. Patients will receive 20 mcg IMCgp100 on C1D1 and 30 mcg IMCgp100 on C1D8. The intra-patient 
escalated dose will then commence at C1D15 and will continue at that same escalated dose level thereafter. 
The Phase 1 portion of the study will be a standard 3+3 dose escalation design. Dose cohort levels are 
presented in Table 6-2. After the dose escalation portion is complete and the MTD or the RP2D-IE is 
identified, the Phase 2 expansion cohorts in mUM will be enrolled. The Phase 2 expansion Cohort A will 
enroll patients with mUM in the second-line setting after disease progression following systemic 
C1D1 
20 mcg
C1D8 
30 mcg 
C1D15 
Intra-patient Escalation  
Cohort 1
Cohort 2
Cohort 3
C1D22 
C2D1 
C2D8 
54 mcg
54 mcg
54 mcg 
54 mcg
64 mcg
64 mcg
64 mcg 
64 mcg
73 mcg
73 mcg
73 mcg 
73 mcg
20 mcg
30 mcg 
20 mcg
30 mcg 
Cohort 1 
Cohort 2 
Cohort 3 
Fixed Dose 


 
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treatment with a checkpoint inhibitor and will recruit approximately 20 patients.  The Phase 2 expansion 
Cohort B will enroll patients with mUM in the second/third-line setting with up to one prior line of LDT 
and will recruit approximately 130 patients. A total of approximately 150 patients will be enrolled into the 
Phase 2 expansion phase of the study. See Figure 3-2. 
 
 
 
 
 
 
 
Figure 3-2 Study Design  
LDT = liver-directed therapy; ORR = objective response rate; RP2D = recommended Phase 2 dose; RP2D-IE = 
recommended Phase 2 dose — intra-patient escalation.  
Phase 1 testing of the intra-patient escalation regimen to identify the RP2D-IE will implement a standard 3+3 design. 
Once the dose is identified in the Phase 1 dose escalation, 2 Phase 2 expansion cohorts will be enrolled in 2 patient 
populations:  (1) Cohort A will enroll patients with 1 systemic treatment regimen containing a checkpoint inhibitor, 
including either a cytotoxic T lymphocyte associated protein-4 (CTLA-4) inhibitor (ipilimumab or tremelimumab) 
and/or a PD-1/programmed death-ligand 1 (PD-L1 inhibitor and any prior LDT, and (2) Cohort B will recruit 
approximately 130 patients to further characterize the safety, tolerability, PK, and anti-tumor response of IMCgp100 
in patients who have been previously treated with 1 or 2 prior lines of therapy in the metastatic or advanced setting 
(including chemotherapy, immunotherapy or targeted therapy) and up to a single line of local, LDT. Prior checkpoint 
inhibitor is acceptable in Cohort B but is not required.  
Additional details on Phase 2 Expansion cohorts are provided in Section 3.2 and Section 5.2. 
These expansion cohorts are designed to further characterize the safety, tolerability, and preliminary PK and anti-
tumor activity of IMCgp100.  
 
Patient Population 
The trial will enroll patients with a diagnosis of advanced UM, defined as histologically confirmed diagnosis 
of UM and metastatic stage IV disease at study entry. In the Phase 1 dose escalation portion of the trial, 
patients are eligible with any prior therapy including systemic treatments or LDT with an Eastern 
Cooperative Oncology Group (ECOG) performance score of 0 or 1 and meeting all additional eligibility 
criteria.  
Enrollment into the Phase 1 dose escalation portion has been completed and RP2D-IE was determined to 
be 68 mcg. Two Phase 2 expansion cohorts will be enrolled in 2 patient populations based on prior 
therapy:   
Phase 2 Expansion B:  IMCgp100 at RP2D 
Up to 2 prior lines; up to 1 prior LDT 
N ~ 130 
Phase 2 Expansion A:  IMCgp100 at RP2D 
Prior checkpoint required; Any prior LDT 
N ~ 20  
Phase 1 
Intra-patient Escalation 
N~18–24 


 
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1. Cohort A:  Patients will have experienced disease progression with 1 systemic treatment 
regimen containing a checkpoint inhibitor, including either a CTLA4 inhibitor (ipilimumab or 
tremelimumab) and/or a PD-1/PD-L1 inhibitor.  Any prior LDT is acceptable in this cohort.  
2. Cohort B:  Patients will have experienced disease progression with 1 or 2 prior lines of therapy in 
the metastatic or advanced setting including chemotherapy, immunotherapy or targeted 
therapy. Only a single line of local, LDT including chemotherapy, radiotherapy, radiofrequency 
ablation or embolization is allowed. A line of LDT is defined as one modality of treatment that is 
administered until completion of treatment or disease progression. For patients who have 
received prior LDT, this will count as a line of therapy. Prior surgical resection of oligometastatic 
liver disease is allowed and is not counted as a line of LDT. A patient may have discontinued 
systemic therapy prior to disease progression if the patient experienced an adverse reaction 
that required treatment discontinuation, as per Investigator’s judgment and applicable labelling. 
Prior checkpoint inhibitor therapy is acceptable but not required in this cohort. 
a. This means patients with the following treatments are eligible under Cohort B: 
 1 systemic therapy and 1 LDT 
 1 – 2 systemic therapies and 0 LDT 
 0 systemic therapy and 1 LDT 
b. Adjuvant therapies and local therapies for treatment of disease outside of the liver do 
not count towards the lines of prior therapy.  
These Phase 2 expansion cohorts are designed to further characterize the safety, tolerability, and 
preliminary PK and anti-tumor activity of IMCgp100.  
Emerging preclinical data (Section 1.3.1) suggest that the residence time of IMCgp100 to the HLA-A*0201 
allele is considerably longer resulting in enhanced effects compared to non-HLA-A*0201 alleles. This is 
borne out in the clinical data (Section 1.4.2), where patients expressing non-HLA-A*0201 alleles appear 
to have fewer T cell mediated toxicities and no clinical responses have been observed. Given these 
preclinical and clinical data, enrollment is limited to patients expressing the HLA-A*0201 allele. 
 
Definition of Study Periods 
The Pre-screening Period will begin once a patient has signed the Pre-screening Informed Consent Form 
(ICF) and concludes with the HLA-A*0201 testing results. A blood test will determine whether the patient 
is HLA-A*0201 positive (eligible) or HLA-A*0201 negative (not eligible). Patients will either be designated 
as pre-screening failure (negative test result or if positive and the patient chooses not to enter the study), 
or eligible for the study (HLA-A*0201 positive) and the patient can proceed and sign the Main Study ICF. 
Patients who re-screen for the trial need not return to the pre-screen period once HLA results are known. 
Patients known to be HLA-A*0201 positive by prior testing done outside the study may complete the pre-
screening and screening periods in parallel. 


 
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The Screening Period will begin once a patient has signed the consent form and concludes with either a 
screen failure decision or initiation of study dosing on C1D1. Patients will not sign the main study ICF until 
the HLA-A2 status is known via central laboratory testing (see Pre-screening Period above). During the 
Screening Period, patients are evaluated against the study inclusion and exclusion criteria (see Section 5) 
and all screening procedures and observations are performed. The screening window for all procedures 
will be 21 days, other than imaging studies which will have a 28-day window. Patients who screen negative 
may re-screen for the trial without re-entering the pre-screen period.  
The Treatment Period will begin with the first treatment in the first cycle with C1D1. For the purpose of 
treatment scheduling, a cycle consists of 4 weeks (28 days).  The Treatment Period consists of the time 
from C1D1 until the end of study treatment.  
The 90-day Safety Follow-up Period consists of the time from the last dose of study medication for a 
period of 90 days. Safety observations during this 90-day Follow-up Period are outlined in Section 7.2.3 
and include reporting of all AEs and all serious adverse events (SAEs) in the same manner as the Treatment 
Period. Anti-neoplastic therapies since discontinuation of study drug will be collected during this follow-
up period. 
The Disease Progression Follow-up Period is defined for all patients who discontinue for reasons other 
than death, progressive disease (PD) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 
v.1.1) or modified irRECIST as outlined below, lost to follow up, withdrawal of consent, or study 
termination. 
 
All patients who discontinue for reasons other than PD per RECIST v1.1 will be followed with 
imaging until evidence of PD per RECIST v.1.1 (see Section 7.2.4 and Section 7.3.1) 
 
For patients who consent to and continue treatment beyond progression per RECISTv.1.1, imaging 
should continue until progression per modified irRECIST (irPD) or treatment discontinuation. 
 
If patients choose not to return for these visits or are unable to do so, every effort should be made 
to contact them or a knowledgeable informant by telephone to determine if the patient has had 
disease progression. . 
 
Patients who discontinue treatment for reasons of disease progression by either RECISTv1.1 or 
modified irRECIST criteria will not enter the Disease Progression Follow-up Period. 
 
Anti-neoplastic therapies since discontinuation of study drug will be collected during this follow-
up period. 
The Survival Follow-up Period will initiate after either the 90-day Follow-up Period (in patients who have 
discontinued for PD) or after the Disease Progression Follow-up Period (for patients discontinuing study 
treatment for reasons other than PD) and continue until death. As possible, all patients will be followed 
for survival until the end of the study is reached. Anti-neoplastic therapies since discontinuation of study 
drug will be collected during this follow-up period. 


 
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End of Treatment  
In all patients in this study, IMCgp100 will be administered IV according to the defined regimen. Reasons 
for discontinuation of study treatment are described in Section 6.10. 
Patients who discontinue treatment will remain in the study and be followed for the overall survival (OS) 
endpoint.  
Each patient’s disease will be assessed for efficacy using 2 sets of criteria:  (1) RECIST v.1.1 and (2) modified 
irRECIST. The objective response rate (ORR) endpoint will be assessed as ORR per RECIST v.1.1; however, 
patients experiencing PD per RECIST v.1.1 criteria may consent to continue to be treated until meeting 
the criteria for unequivocal, confirmed PD by modified irRECIST as defined in Section 13.2.1. 
Please refer to Section 6.9 for details regarding imaging assessment of PD for purposes of treatment 
discontinuation.  
 
Definition of End of Study 
The end of the study will be when a minimum of 80% of the patients have completed the follow-up for 
disease progression or discontinued the study for any reason, and all patients have completed treatment 
and the 90-day Follow-up Period, or if the study is terminated early. 
An individual patient may end participation in the study for reasons described in Section 6.11. Please refer 
to Section 9, Statistical Methods and Data Analysis for details of timing of the primary analysis and final 
reporting of data. 
 
Early Study Termination 
The study can be terminated at any time for any reason by the Sponsor. Should this be necessary, any 
ongoing patient should be seen as soon as possible for End of Treatment (EOT) visit and the assessments 
should be performed as described in Table 7-1 for the EOT visit.  
The investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. Under guidance of the 
Sponsor, the investigator will be responsible for informing the Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) of the termination of the trial. 


 
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4 STUDY OBJECTIVES AND ENDPOINTS 
 
Primary Objective 
Phase 1 dose escalation:  The primary objective is to identify the MTD and/or the RP2D of IMCgp100 in 
the intra-patient dose escalation regimen (RP2D-IE). 
Phase 2 dose expansion:  The primary objective is to estimate the ORR by independent central review 
(ICR) based on RECISTv.1.1 in patients with metastatic UM who are treated with the RP2D-IE of IMCgp100. 
 
Secondary Objectives 
 
To characterize the safety and tolerability of IMCgp100 in the intra-patient dose escalation regimen   
 
To characterize the PK profile of single-agent IMCgp100 in the intra-patient dose escalation regimen 
 
To assess the anti-tumor efficacy of IMCgp100 with the parameters of ORR [Phase 1], OS, progression-
free survival (PFS), disease control rate (DCR), time to response, and the duration of response (DOR)  
 
To evaluate the incidence of anti-IMCgp100 antibody formation following multiple infusions of 
IMCgp100 in the intra-patient dose escalation regimen 
 
To determine the rate and duration of minor responses (MinR) (defined as tumor response with a 
10%–29% reduction in the sum of longest diameters [SLD]) 
 
To determine immune responses (as assessed by area under the tumor response curve [AUC]) 
 
Exploratory Objectives 
 
  
 
  
 
 
 
 
 
 


 
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Primary Endpoints 
Phase 1 dose escalation:  The primary endpoint is incidence of DLT. 
Phase 2 dose expansion:  The primary endpoint is ORR by RECISTv.1.1 assessed by ICR. 
 
Secondary Endpoints 
 
Tolerability:  Dose interruptions, reductions, and dose intensity of all administered agents 
 
Serum PK parameters (e.g., AUC, Cmax, T, t1/2) 
 
Tumor response endpoints (ORR [Phase 1], PFS, DCR, DOR, time to response) as determined by RECIST 
v.1.1  
o Note:  For the Phase 2 expansion cohorts, primary assessment of tumor-based endpoints 
will be provided by an ICR. Investigator assessment data will also be collected for both 
Phase 1 dose escalation cohort (primary assessment) and Phase 2 expansion cohorts 
(secondary assessment)   
 
OS 
 
Assessments of anti-IMCgp100 antibody formation 
 
Minor tumor responses (10% to 29% reduction in the SLD) and immune responses (as assessed by 
AUC) 
 
Exploratory Endpoints 
 
  
 
 
 
 
 


 
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Objective 
Endpoint 
Primary 
Phase 1 dose escalation:  To identify the 
MTD and/or the RP2D of IMCgp100 in the 
weekly RP2D-IE 
Phase 2 dose expansion:  To estimate the 
ORR by ICR based on RECISTv.1.1 in 
patients with advanced UM who are treated 
with the RP2D of IMCgp100 in the RP2D-IE 
Phase 1 dose escalation:  Incidence of DLT 
 
Phase 2 dose expansion:  ORR by RECISTv.1.1 assessed by 
ICR 
Secondary 
To characterize the safety and tolerability of 
IMCgp100 in the intra-patient dose 
escalation regimen 
Tolerability:  Dose interruptions, reductions and dose intensity of all 
administered agents 
To characterize the PK profile of single-
agent IMCgp100 in the intra-patient dose 
escalation regimen 
Serum PK parameters (e.g., AUC, Cmax, Tmax, t1/2) 
To assess the anti-tumor efficacy of 
IMCgp100 with the parameters of ORR 
[Phase 1], OS, PFS, DCR, time to response, 
and the DOR   
 
ORR (Phase 1), PFS, DCR, DOR, and time to response 
as per RECISTv.1.1 
 
For the Phase 2 expansion cohorts, primary assessment of 
tumor-based endpoints will be provided by an ICR. 
Investigator assessment data will also be collected for both 
Phase 1 dose escalation cohort (primary assessment) and 
Phase 2 expansion cohorts (secondary assessment)  
 
Overall survival 
To evaluate the incidence of anti-IMCgp100 
antibody formation following multiple 
infusions of IMCgp100 in the intra-patient 
dose escalation regimen 
Assessments of anti-IMCgp100 antibody formation 
To determine the rate and duration of MinR 
(defined as tumor response with a 10%–
 
Minor tumor responses (10% to 29% reduction in the SLD) 
Table 4-1 
Objectives and Related Endpoints 


 
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Objective 
Endpoint 
29% reduction in the SLD) and immune 
responses  
 
Immune responses (as assessed by area under the tumor 
response curve [AUC]) 
Exploratory 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
AE = adverse event; AUC = area under the curve; Cmax = maximum observed serum concentration; ctDNA = 
circulating tumor deoxyribonucleic acid; DLT = dose limiting toxicity; DOR = duration of response; ECG = 
electrocardiogram;
 
  ICR = independent central review; irRECIST 
= immune-related RECIST = Response Evaluation Criteria in Solid Tumors; MDSC = myeloid-derived suppressor 
cell; MinR = duration of minor responses; MTD = maximum tolerated dose; ORR = objective response rate; OS = 
overall survival; PD-L1 = programmed death-ligand 1; PFS = progression-free survival; PK = pharmacokinetic; 
RECIST = Response Evaluation Criteria in Solid Tumors; RP2D = recommended Phase 2 dose; RP2D-IE = 
recommended Phase 2 dose — intra-patient escalation; SAE = serious adverse event; SLD = sum of the longest 
diameters; t1/2 = half-life; Tmax = time of maximum concentration; UM = uveal melanoma. 


 
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5 POPULATION SELECTION CRITERIA 
 
Patient Population 
This study will be conducted in patients with metastatic UM with any prior systemic therapy in the 
metastatic and advanced setting in the dose escalation cohorts. Two Phase 2 expansion cohorts will be 
enrolled in 2 patient populations defined by prior therapy for metastatic UM.  Given the mechanism of 
action of IMCgp100, the study is limited to patients with the HLA-A*0201 subtype.  
The investigator or designee must ensure that only patients who meet all the following inclusion and none 
of the exclusion criteria are offered treatment in the study.  
 
Inclusion Criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 
1. Male or female patients age ≥ 18 years of age at the time of informed consent 
2. Ability to provide and understand written informed consent prior to any study procedures  
3. Histologically or cytologically confirmed diagnosis of metastatic UM 
4. Surgically sterile patients or patients of child-bearing potential who agree to use highly effective 
methods of contraception during study dosing and for 6 months after last dose of study drug 
5. Life expectancy of > 3 months as estimated by the investigator 
6. HLA-A*0201 positive by central assay 
7. ECOG Performance Status of 0 or 1 at Screening 
8. Patients must have disease (measurable or non-measurable acceptable) according to RECIST v.1.1 
criteria in Phase 1 dose escalation cohorts. Patients must have measurable disease in the Phase 2 
dose expansion cohorts 
9. Phase 1 dose escalation cohorts only:  any prior therapy is acceptable 
Prior therapy in Phase 2 expansion cohorts:  
 
Cohort A:  Patients will have experienced disease progression with 1 systemic treatment 
regimen containing a checkpoint inhibitor, including either a CTLA4 inhibitor (ipilimumab or 
tremelimumab) and/or a PD-1/PD-L1 inhibitor. Any prior LDT is acceptable in this cohort 
 
Cohort B:  Patients will have experienced disease progression with 1 or 2 prior lines of therapy 
in the metastatic or advanced setting including chemotherapy, immunotherapy or targeted 
therapy. Only a single line of local, LDT including chemotherapy, radiotherapy, radiofrequency 
ablation or embolization is allowed. A line of LDT is defined as one modality of treatment that 
is administered until completion of treatment or disease progression. For patients who have 
received prior LDT, this will count as a line of therapy. Prior surgical resection of 
oligometastatic liver disease is allowed and is not counted as a line of LDT. A patient may have 


 
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discontinued systemic therapy prior to disease progression if the patient experienced an 
adverse reaction that required treatment discontinuation, as per Investigator’s judgment and 
applicable labelling. Prior checkpoint inhibitor therapy is acceptable but not required in this 
cohort. 
a. This means patients with the following treatments are eligible under Cohort B: 
o 1 systemic therapy and 1 LDT 
o 1 – 2 systemic therapies and 0 LDT 
o 0 systemic therapy and 1 LDT 
b. Adjuvant therapies and local therapies for treatment of disease outside of the liver do 
not count towards the lines of prior therapy.  
10. All other relevant medical conditions must be well-managed and stable, in the opinion of the 
investigator, for at least 28 days prior to first administration of study drug 
 
Exclusion Criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Presence of symptomatic or untreated central nervous system (CNS) metastases, or CNS 
metastases that require doses of corticosteroids within the prior 3 weeks to Study Day 1. 
Asymptomatic and adequately treated CNS metastases are not exclusionary 
2. History of severe hypersensitivity reactions to other biologic drugs or monoclonal antibodies 
3. Patient with any out-of-range laboratory values defined as: 
 
Serum creatinine > 1.5 x upper limit of normal (ULN) and/or creatinine clearance (calculated 
using Cockcroft-Gault formula, or measured) < 50 mL/min 
 
Total bilirubin > 1.5 x ULN, except for patients with Gilbert’s syndrome who are excluded if 
total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN 
 
ALT > 3 x ULN 
 
AST > 3 x ULN 
 
Absolute neutrophil count < 1.0 x 109/L 
 
Absolute lymphocyte count:  (1) Phase 1 and Phase 2 Expansion Cohort A:  Absolute 
lymphocyte count < 0.5 x 109/L; (2) Phase 2 Expansion Cohort B:  Absolute lymphocyte count 
< 1.0 x 109/L   
 
Platelet count < 75 x 109/L 
 
Hemoglobin < 8 g/dL 
 
Potassium, magnesium, corrected calcium or phosphate abnormality of National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) > grade 1 


 
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4. Dose escalation only:  Presence of high tumor burden, defined as liver replacement of > 60% 
hepatic organ volume with tumor 
5. Clinically significant cardiac disease or impaired cardiac function, including any of the following: 
 
Clinically significant and/or uncontrolled heart disease such as congestive heart failure (New 
York Heart Association grade ≥ 2), uncontrolled hypertension, or clinically significant 
arrhythmia currently requiring medical treatment 
 
QTc > 470 msec on screening electrocardiogram (ECG) or congenital long QT syndrome 
 
Acute myocardial infarction or unstable angina pectoris < 6 months prior to Screening 
6. Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for 
infection must have completed therapy before Screening 
7. Known history of human immunodeficiency virus (HIV) infection. Testing for HIV status is not 
necessary unless clinically indicated or if required by local regulations 
8. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional protocol. Testing 
for HBV or HCV status is not necessary unless clinically indicated or the patient has a history of 
HBV or HCV infection or if required by local regulations 
9. Patients receiving systemic treatment with systemic steroid therapy or any other 
immunosuppressive medication at any dose level that would interfere with the action of the study 
drugs in the opinion of the investigator   
10. Malignant disease, other than that being treated in this study. Exceptions to this exclusion include 
the following:  malignancies that were treated curatively and have not recurred within 2 years 
prior to study treatment; completely resected basal cell and squamous cell skin cancers; any 
malignancy considered to be indolent and that has never required therapy; and completely 
resected carcinoma in situ of any type 
11. Any medical condition that would, in the investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns, compliance with clinical study 
procedures or interpretation of study results 
12. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic or 
immunotherapy agents that can present with major delayed toxicity (e.g., anti-CTLA-4), 4 weeks 
is indicated as washout period 
13. Presence of NCI CTCAE ≥ grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, 
which are excluded if ≥ NCI CTCAE grade 3 and hypothyroidism adequately managed with 
replacement therapy) due to prior cancer therapy 
14. Patients with adrenal insufficiency or patients currently requiring chronic, systemic corticosteroid 
therapy at any dose for longer than 2 weeks. Local steroid therapies (e.g., otic, ophthalmic, intra-
articular, or inhaled medications) are acceptable   


 
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15. Major surgery within 2 weeks of the first dose of study drug (minimally invasive procedures such 
as bronchoscopy, tumor biopsy, insertion of a central venous access device, and insertion of a 
feeding tube are not considered major surgery and are not exclusionary) 
16. Radiotherapy within 2 weeks of the first dose of study drug, with the exception of palliative 
radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor 
mass  
17. Use of hematopoietic colony-stimulating growth factors (e.g., G-CSF, GMCSF, M-CSF) ≤ 2 weeks 
prior to start of study drug. Patients must have completed therapy with hematopoietic colony-
stimulating factor at least 2 weeks before the first dose of study drug is given. An erythroid-
stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of 
study treatment and the patient is not red blood cell transfusion dependent 
18. Pregnant, likely to become pregnant, or lactating women (where pregnancy is defined as the state 
of a female after conception and until the termination of gestation) 
19. Women of child-bearing potential who are sexually active with a non-sterilized male partner, 
defined as all women physiologically capable of becoming pregnant, unless they are using highly 
effective contraception during study treatment, must agree to continue using such precautions 
for 6 months after the final dose of investigational product; cessation of birth control after this 
point should be discussed with a responsible physician. Highly effective methods of contraception 
are described in Section 6.6. 
20. Male patients must be surgically sterile or use double barrier contraception method from 
enrollment through treatment and for 6 months following administration of the last dose of study 
drug 
21. Patients may not have been included in any prior IMCgp100 trial, regardless of assigned treatment 
cohort 
 


 
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6 STUDY TREATMENTS AND ADMINISTRATION 
 
Study Treatment 
For this study, the investigational drug refers to IMCgp100. Study drug will be supplied by the Sponsor, 
Immunocore. 
All dosages prescribed and dispensed to patients and all dose changes during the study must be recorded 
on the Dosage Administration Record electronic case report form (eCRF). 
2 
IMCgp100 
Concentrate for solution for 
infusion 
 (single use vials) 
20 mcg Cycle 1 Day 1 and 30 
mcg Cycle 1 Day 8 then 68 
mcg from Cycle 1 Day 15 and 
thereafter 
 
Every week 
For all study medication administration, a physician must be present at the site or immediately available 
to respond to emergencies during all administrations of all study medications. Fully functional 
resuscitation facilities should be available.  
 IMCgp100  
IMCgp100 will be supplied as a liquid formulation for dilution prior to administration.  IMCgp100 will be 
administered via IV infusion over 15–20 minutes QW.  Each vial is designed for single use only and is not 
to be used to treat more than one patient for more than one dose.  
6.1.1.1 IMCgp100 0.5 mg/mL drug product  
IMCgp100 0.5 mg/mL drug product will be provided as a sterile, frozen solution in glass vials. Detailed 
instructions for dose preparation and administration are provided in the study pharmacy manual and a 
summary is provided below. 
Table 6-1 
Dose and Treatment Schedule 
Phase 
Study 
Treatments 
Pharmaceutical Form and 
Route of Administration 
Dose 
Frequency 
and/or 
Regimen 
I 
IMCgp100 
Concentrate for solution for 
infusion (single use vials) 
20 mcg Cycle 1 Day 1 and 30 
mcg Cycle 1 Day 8 then, 
Dose as determined by cohort 
from Cycle 1 Day 15 and 
thereafter (refer to Table 6-2 
for Dose Levels) 
Every week  


 
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 Dispensing, Dose Preparation and Administration  
IMCgp100 will be supplied as concentrate for solution for infusion and require dilution prior to 
administration. Detailed instructions for dose preparation and administration are provided in the study 
pharmacy manual and/ or on the relevant pharmacy handling instructions. Once prepared for 
administration, the final infusion bag containing IMCgp100 must be administered within 4 hours at room 
temperature from the time of initial puncture of the supplied drug vial. 
The target duration of administration of IMCgp100 will be 15–20 minutes. The entire content of the IV 
bag will be infused using an infusion pump. The IV line should be flushed after the contents of the IV bag 
are fully administered according to institutional policy to ensure the full dose is administered. It must be 
documented if the line was not flushed. 
 
Summary of Intra-patient Dose Escalation Treatment Regimen 
Patients enrolled in this study will receive treatment with single-agent IMCgp100 on C1D1 and C1D8 at 20 
mcg and 30 mcg per week, respectively. The majority of moderate-to-severe toxicity associated with 
IMCgp100 in the FIH study was observed at these 2 dose time points and included hypotension, rash, 
pruritus, fever, and chills (please refer to Section 1.4, Clinical Experience with IMCgp100 for a full 
discussion of the safety data with IMCgp100). After this initial dosing period, beginning at C1D15, patients 
will receive an escalated dose of IMCgp100 according to the cohort into which they are enrolled (please 
see Table 6-2 below, for dose levels to be tested). This escalated dose administered at C1D15 will be the 
dose used for the remainder of the treatment period unless dose reduction is implemented for toxicity. 
See schematic for intra-patient dose escalation regimen described in Section 3.1 and Figure 3-1.  
In this intra-patient escalation regimen, all patients will require overnight inpatient hospitalization and a 
minimum of pre-dose and monitoring vital signs every 4-hours after the first administration of IMCgp100 
(C1D1), after the second administration (C1D8), and after the escalated dose of IMCgp100 on C1D15 is 
administered. For the first 3 administrations of IMCgp100, patients should be monitored for at least 16 
hours after dosing. “Inpatient hospitalization” refers to a facility with fully functional resuscitation 
facilities, 24 hour monitoring and physician availability.  
Inpatient monitoring at Cycle 1 Day 22 (C1D22) will be determined by the toxicity observed in the C1D1–
C1D15 doses as follows:   
1. If the escalated dose at C1D15 administered as an inpatient does not raise safety concerns (and 
the patient does not experience an adverse reaction involving hypotension of grade 2 or greater), 
the subsequent dose at C1D22 and all subsequent doses can be administered on an outpatient 
basis 
2. If the patient experiences hypotension requiring any medical intervention (Common Terminology 
Criteria for Adverse Event [CTCAE] grade 2 or greater) at C1D15, then the C1D22 dose must be 
administered with inpatient monitoring, similar to C1D1–C1D15. If the patient does not 
experience hypotension requiring medical intervention at the C1D22 dose administered as an 
inpatient, then all subsequent doses can be administered on an outpatient basis  


 
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3. Hospitalization at other days (e.g., Cycle 2 and beyond) are determined at the discretion of the 
principal investigator based on the patient’s history and tolerance for the initial doses of the study 
medication with the exception of patients experiencing a treatment delay (please refer to bullet 
5 below) 
4. Until Cycle 2 Day 15 (C2D15), patients who have experienced a prior CTCAE grade 3 or 4 
hypotension event with IMCgp100 dosing and are receiving a dose in the outpatient setting, must 
be observed in the clinic for a minimum of 8 hours after completion of the IMCgp100 dose.  
5. Patients experiencing a break or delay in treatment for any reason of more than 2 weeks AND 
have a history of a grade 3 or 4 hypotension event with IMCgp100 dosing during the first weeks 
of treatment will be monitored as an inpatient for the dose subsequent to the break in dosing, 
regardless of the timing of the break in dosing. 
Due to the risk of hypotension, all patients receiving anti-hypertensive medications must discontinue all 
anti-hypertensive therapy for 24 hours prior to dosing and for 24 hours after dosing for the first 6 QW 
doses of IMCgp100 unless discussed and agreed with the Sponsor’s Medical Monitor. After the sixth 
weekly dose, anti-hypertensive therapy can be restarted on a continuous basis thereafter with the dosing 
of IMCgp100 (eliminating the 24 hour hold during IMCgp100 dosing) at the discretion of the principal 
investigator. 
In addition, due to the risk of hypotension, IV fluids may be administered prior to IMCgp100 
administration and, if given, IV fluids will be recorded as a concomitant medication in the eCRF. The 
administration of IV fluids should be guided by clinical evaluation and the volume status of the patient. 
Pruritus is a common adverse event with IMCgp100, so premedication with an antihistamine may be 
considered. See Table 6-3 for further recommendations regarding treatment of skin toxicity. If a patient 
experiences an infusion reaction, he/she may receive premedication on subsequent dosing days after 
consultation with the Sponsor Medical Monitor. Pre-medications should include, but are not limited to, 
paracetamol/acetaminophen and an antihistamine. Corticosteroid premedication should be avoided; 
corticosteroids should only be considered if the paracetamol/acetaminophen and antihistamine 
combination is not effective and only after consultation with the Sponsor Medical Monitor. 
If 2 or more patients experience moderate-to-severe acute infusion reactions on C1D1 or if > 25% of 
patients experience mild infusion reactions, then mandatory primary prophylaxis regimens (i.e., before 
dosing on C1D1 or C1D15) will be instituted for subsequent patients beginning treatment after discussion 
and agreement among principal investigators and the Sponsor. Primary and secondary prophylaxis 
regimens will include both paracetamol/acetaminophen and an antihistamine. The decision taken to 
mandate primary prophylaxis will be communicated in writing to all principal investigators participating 
in the study.   
Acute allergic reactions should be treated as needed using institutional guidelines. In the event of 
anaphylactic/anaphylactoid reactions, any therapy necessary to restore normal cardiopulmonary status 
should be implemented immediately. Such acute allergic reactions will be reported to the Sponsor in an 
expedited manner. These should be designated as reportable as a SAE regardless of hospitalization as 
medically important events. Please refer to SAE reporting section for details. The individual symptoms of 


 
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the infusion-related reaction should be captured in order to best characterize the study drug infusion 
reactions, unless the investigator considers another category, such as “allergic reaction,” “anaphylaxis,” 
or “cytokine release syndrome” more appropriate in a specific situation. 
 
Dose Escalation Guidelines 
 Dose-limiting Toxicities Observation Period 
The DLT observation period for the Phase 1 cohorts will be the first cycle during IMCgp100 dosing (C1D1 
until C1D28).  
 Starting Dose Rationale 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 Dose Levels 
This study will begin with Phase 1 dose escalation of the intra-patient escalation dosing regimen to assess 
the safety and tolerability of the C1D15 intra-patient escalation. 
 
 
 
 
  


 
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 Dose Escalation Guidelines 
Three to 6 patients will be enrolled in sequentially enrolling dose cohorts (see Table 6-2 dose levels). In 
each cohort, patients will be treated during Cycle 1 with IMCgp100 as a single agent (Days 1 and 8 of Cycle 
1, all patients receive the 20 and 30 mcg, retrospectively). At C1D15, the intra-patient dose escalation will 
begin. The study will begin with Cohort 1 (See Table 6-2 dose levels) receiving dose level 1 (54 mcg) at 
CD15 and thereafter. Other cohorts enrolling after Cohort 1 will follow the dose escalation guidelines. 
Cohorts will enroll to escalation by increments of 10 mcg until an MTD and/or RP2D-IE for the intra-patient 
dose escalation regimen is identified.  
An individual cohort will initially enroll 3 to 6 patients. If none of the 3 patients experiences a DLT, then 
dose escalation decision may proceed after agreement among study team members (participating 
investigators and Sponsor) within the DETC. The decision to escalate the dose will be determined based 
on available toxicity, PK, and pharmacodynamic data following a discussion among members of the study 
team (all participating investigators and Sponsor Medical Monitor) during DETC. The cohort will be 
expanded to 6 patients if DLT is observed during the DLT period according to the dose escalation rules 
noted below. If toxicity is managed adequately to resume IMCgp100 dosing, patients experiencing DLT 
may continue treatment with IMCgp100 only after agreement with the Sponsor Medical Monitor. Patients 
in the Phase 1 cohorts will be considered evaluable for dose escalation decisions (DLT Analysis Set) if they 
receive a minimum of 3 doses of IMCgp100 (with 2 of the 3 doses at the escalated level of C1D15 and 
thereafter) or have experienced DLT during the DLT observation period.  
Dose-escalation in the study will occur after the study team (Sponsor and investigators) have jointly 
reviewed available safety data for the 3 to 6 patients at the current dose level at a safety team DETC. The 
decision to dose-escalate will be taken by the study team (participating investigators and the Sponsor 
Medical Monitor). Additional cohorts may be added if necessary to explore alternate/intermediate dose 
levels if deemed necessary by the members of the dose escalation teleconference.  


 
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6.3.4.1 Dose Escalation Decision Making 
Dose-escalation decisions will be made based on treatment-emergent AE, clinical laboratory data, and 
available PK, and pharmacodynamic data after all patients in a cohort complete the 28-days of study 
treatment in Cycle 1. Safety data from patients on preceding cohorts will also be taken into consideration. 
The data will be reviewed and a decision taken whether or not to proceed to the next dose cohort (at the 
planned or an alternative dose level), whether more patients are required to be dosed at the dose level 
under review or whether the MTD and/or the optimal RP2D-IE has been reached.  
The following dose-escalation rules will be used: 
If none of the first 3 evaluable patients experiences a DLT by the end of the DLT observation period, the 
dose will be escalated and the next cohort of patients can start treatment at the next highest dose level. 
 
If 1 of the first 3 patients experiences a DLT in Cycle 1, the cohort will be expanded to 6 patients. 
If none of these additional patients experiences a DLT, then the dose will be escalated to the next 
higher dose level 
 
If 2 or more patients in the dose level experience a DLT in the DLT observation period, then the 
MTD has been exceeded and 3 more patients will be treated at the next lower dose level, if only 
3 patients were previously treated at that dose level  
 
If 0 or 1 DLT is observed at this lower dose level, this dose will be determined to be the MTD  
 
If 2 DLTs occur at this level, the next lower dose will need to be evaluated similarly  
 
A minimum of 6 patients will be evaluated at the dose level identified as the RP2D-IE in this study   
6.3.4.2 Definition of MTD and RP2D-IE 
The MTD is defined as the highest dose level with an observed incidence of DLT in fewer than 33% of the 
patients enrolled in a cohort level. If all evaluated dose levels demonstrate an observed incidence of DLT 
in fewer than 33% of patients, the MTD has not been reached. If this proves to be the case, then a total 
of 6 patients will be treated at the highest dose tested to gain additional safety data before proceeding to 
the dose-expansion part of the study. If a DLT occurs at the MTD, a total of 6 patients must be treated at 
the MTD.  
Determination of the RP2D-IE will be based on the sum of the safety, tolerability, pharmacodynamic and 
PK data, as well as preliminary efficacy data emerging over the course of the Phase 1 testing. The MTD 
and RP2D-IE may be not be the same dose level for implementation in the UM expansion cohort.  
The RP2D-IE will be based on the sum of the safety, tolerability, pharmacodynamic, and PK data, as well 
as preliminary efficacy data emerging over the course of the Phase 1 testing. The RP2D-IE will be defined 
as the dose level selected for testing in the expansion cohort by the study team, based on all available 
safety, tolerability, PK, and pharmacodynamic data. The MTD and RP2D-IE may not be the same dose 
level; the RP2D-IE will be the same dose or a lower dose than an identified MTD. If the MTD and RP2D are 
different, the RP2D-IE will be implemented in the expansion cohorts. A minimum of 6 patients will be 


 
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treated at the identified RP2D-IE for the DLT period before the expansion cohorts with this dose can begin 
enrollment. 
During the course of the UM expansion cohorts, if the rate of grade 3 and/or grade 4 toxicity is considered 
related to the study drugs and meeting the definition of DLT is higher than 30%, a safety teleconference 
will be convened with the study team (Sponsor and investigators) to determine if the cohort should 
continue enrollment.  
6.3.4.3 Replacement of Patients 
Patients will be replaced in the Phase 1 cohorts according to the guidelines for Phase 1 dose escalation. 
Patients deemed not eligible for the DLT Analysis Set in Phase 1 will be replaced.  
 
Definition of Dose-limiting Toxicities 
A DLT is defined as an AE or abnormal laboratory value assessed as having a suspected relationship to 
study drug, and unrelated to disease, disease progression, inter-current illness, or concomitant 
medications that occurs within the first cycle of treatment, and meets any of the criteria included in  
Table 6-3. NCI CTCAE version 4.03 will be used for all grading unless otherwise specified. The investigator 
must notify the Sponsor immediately of any unexpected NCI CTCAE grade ≥ 3 AEs or laboratory 
abnormalities. Prior to enrolling patients into a higher dose level, all NCI CTCAE grade ≥ 2 AEs will be 
reviewed for all patients at the current dose level by the study team at the DETC.  


 
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Table 6-3 
Criteria for Defining Dose Limiting Toxicities 
DLTs include any related AE of NCI CTCAE grade 3 or higher occurring in the first cycle of weekly 
IMCgp100, during the dose escalation Phase 1 part of the study with the following exceptions: 
Hematology 
Neutropenia is a DLT if it is NCI CTCAE grade 4 
Thrombocytopenia is a DLT if it is NCI CTCAE grade 4  
Anemia is a DLT if it is NCI CTCAE grade 4 
Lymphopenia of grade > 3 persistent for more than 14 days or the presence of 
an infection indicating clinically significant lymphopenia 
Febrile neutropenia of grade > 3 is a DLT 
Hepatic 
NCI CTCAE grade ≥ 2 total bilirubin with NCI CTCAE grade ≥ 2 ALT is a DLT  
NCI CTCAE grade 3 elevation of ALT and/or AST is a DLT if a concurrent 
elevation of bilirubin is observed (> grade 1) or if the elevated ALT and/or AST 
is not resolved to grade ≤ 1 within 72 hours  
Grade 4 elevation of ALT and/or AST is a DLT 
Gastrointestinal 
Nausea and vomiting are DLTs if they are NCI CTCAE grade ≥ 3 for > 2 days 
despite optimal anti-emetic therapy 
Diarrhea is a DLT if it is NCI CTCAE grade ≥ 3 for > 2 days despite optimal anti-
diarrhea treatment 
Hypotension 
NCI CTCAE grade 3 hypotension is a DLT if not resolved to < grade 1 within 24 
hours of the dose administration.  
Any event of hypotension requiring pharmacologic blood pressure support of any 
duration is a DLT.   
NCI CTCAE grade 4 hypotension of any duration is a DLT   
Hypertension 
NCI CTCAE grade 3 hypertension is a DLT if it persists > 7 days despite 
treatment.  
Grade 4 hypertension of any duration is a DLT 
Infection 
NCI CTCAE grade 3 infection or fever in the absence of neutropenia are DLTs if 
they persist > 5 days. Grade 4 infection of any duration is a DLT 
Tumor flare 
Grade 3 inflammatory reaction at a tumor site associated with a local anti-tumor 
immune response is a DLT if not resolved to grade ≤2 within 7 days 
Electrolytes 
NCI CTCAE grade 3 electrolyte abnormalities are DLTs if they persist > 7 days 
despite treatment or are clinically significant. Grade 4 electrolyte abnormality of 
any duration is a DLT 
Rash and/or 
photosensitivity 
NCI CTCAE grade 3 rash is a DLT if rash persists > 7 days despite optimal 
treatment.  
Grade 4 cutaneous toxicity of any duration is a DLT 
Fatigue 
Fatigue is a DLT if it is NCI CTCAE grade ≥ 3 and lasts > 7 days 
Infusion-related 
reaction 
Grade 3 infusion-related reaction will not be considered a DLT if resolved with 
appropriate medical management within 6 hours of occurrence. Grade 4 infusion 
reaction is a DLT 
Other AEs 
Other clinically significant toxicities, including a single event or multiple 
occurrences of the same event that lead to a dosing delay of > 7 days in Cycle 
1, may be considered to be DLTs by the investigators and Sponsor, even if not 


 
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Concomitant Therapy 
Concomitant therapy will be continuously monitored through the 90-day safety follow up. 
 Permitted Concomitant Therapy 
Concomitant medications and therapies deemed necessary for the supportive care and safety of the 
patient are allowed in general. Examples include anti-diarrheal medications, anti-emetics, or electrolyte 
supplementation.  
Patients must be told to notify the investigational site staff about any new medications, herbal remedies, 
or dietary supplements that he or she takes after the start of the study treatment, regardless of treatment 
duration. All concomitant medications and significant non-drug therapies (including physical therapy, 
herbal or natural medications, and blood transfusions) administered during the study must be listed on 
the Concomitant Medications eCRF.  
IV hydration required to manage toxicity associated with any of the study medications (e.g., hypotension) 
and any IV hydration administered prior to study drug dosing should be recorded in the Concomitant 
Medications eCRF.  
 Permitted Concomitant Therapy Requiring Caution 
Treatment with hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF, M-CSF or 
erythroid stimulating agents) may not be initiated during the first cycle in any arm of the study, unless the 
patient has already experienced a DLT. If a patient is using erythropoiesis-stimulating agent prior to 
enrollment (beginning at least 2 weeks before start of study treatment), they may continue at the same 
dose. 
Anti-coagulant therapy is permitted if the patients are already at stable doses of warfarin or stable doses 
of low molecular weight heparin for > 2 weeks at time of first dose. Prophylactic use of low molecular 
weight heparin during the inpatient hospitalization is allowed. International normalized ratio should be 
monitored as clinically indicated per investigator’s discretion. Ongoing anti-coagulant therapy should be 
temporarily discontinued to allow tumor biopsy according to the institutional guidelines.  
Anti-hypertensives are allowed as concomitant medications; however, because transient hypotension has 
occurred during infusions of IMCgp100 and monoclonal antibodies, treatment with anti-hypertensives 
should be held 24 hours before and 24 hours after IMCgp100 in the first 6 weeks of treatment and 
thereafter at the discretion of the principal investigator, unless discussed and agreed with the Sponsor’s 
Medical Monitor.  
NCI CTCAE grade 3 or higher. Infusion reactions will not be considered as dose 
limiting because they are idiosyncratic and not related to dose 
AE = adverse event; ALT = alanine aminotransferase; DLT = dose limiting toxicity; NCI CTCAE = National 
Cancer Institute Common Terminology Criteria for Adverse Events.  


 
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 Prohibited Concomitant Therapy 
During the course of the study, patients may not receive other additional investigational drugs, agents, 
devices, chemotherapy, or any other therapies that may be active against cancer. Additionally, no other 
systemic therapeutic monoclonal antibodies, except for denosumab and tocilizumab if required for 
patient care, and no immunosuppressive medication may be administered while on this study, unless 
prescribed to manage toxicity. While systemic corticosteroid therapy will interfere with the mechanism 
of action of the study medications, its use is recommended in some settings.  
The use of systemic corticosteroid therapy is permitted/recommended in the following settings:  (1) 
infusion reactions, (2) immune-mediated toxicities and toxicity management as directed in Table 6-5 (e.g., 
hypotension not resolving with fluid support), and (3) replacement-dose steroids in the setting of adrenal 
insufficiency (patients with a pre-existing history of adrenal crisis are excluded from study participation, 
see Section 5.3 Exclusion Criteria). Any additional uses of systemic corticosteroid therapy during the 
course of the study should be discussed with the Sponsor Medical Monitor. 
 
Contraception 
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, 
can be included in the study provided they are using highly effective methods of contraception during 
dosing and for 6 months after the last dose of IMCgp100. 
Highly effective contraception methods include the following: 
 
Total abstinence from sexual relations for the duration of the treatment when applicable to the 
lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
 
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or 
tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, 
this applies only when the reproductive status of the woman has been confirmed by follow-up 
hormone level assessment 
 
Male sterilization (at least 6 months prior to Screening). For female patients on the study the 
vasectomized male partner should be the sole partner for that patient 
 
The combination of any 2 of the following methods when both are used simultaneously: 
o Use of oral, injected, or implanted hormonal methods of contraception or other forms of 
hormonal contraception that have comparable efficacy (failure rate < 1%), for example 
hormone vaginal ring or transdermal hormone contraception 
o Placement of an intrauterine device or intrauterine system 
 


 
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o Barrier methods of contraception:  condom or occlusive cap (diaphragm or cervical/vault 
caps) when used with spermicidal foam, gel, film, cream, or used of a spermicidal vaginal 
suppository 
 
Patient Numbering and Treatment Assignment 
 Patient Numbering 
Each patient is identified in the study by a number that is assigned when the patient is first enrolled for 
Screening. The patient number is retained as the primary identifier for the patient throughout 
participation in the trial. The patient number consists of the center number assigned by the Sponsor and 
a sequential patient number suffix so that each patient is numbered uniquely across the entire database. 
Patient numbers will be assigned by the Sponsor via the interactive response technology system at the 
time of Screening.  
 Treatment Assignment and Randomization 
Patients enrolled in the Phase 1 portion of the study will be assigned to the appropriate open Phase 1 
cohort by the Sponsor. Patients enrolled in the expansion cohort will be assigned by the Sponsor. 
Assignments will be coordinated via the interactive voice response system for the study. 
 
Study Drug Packaging/Labelling, Preparation and Dispensation 
Further instructions for the preparation and dispensation of IMCgp100 are described in the study 
Pharmacy Manual, relevant Pharmacy Handling Instructions and Section 6.1 Study Treatment.  
Packaging and labelling details are outlined in the study Pharmacy Manual and relevant Pharmacy 
Handling Instructions.  
All dosages prescribed to the patient and all dose changes during the study must be recorded on the 
Dosage Administration Record eCRF. 
 Study Drug Compliance and Accountability 
Study treatment will be administered to the patient by the trained study site staff at the study sites and 
as outlined in the study Pharmacy Manual and Section 6.1. Compliance with the prescribed regimen will 
be assured by administration of the study treatment under the supervision of investigator or his/her 
designee. 
The investigator or designee must maintain an accurate record of the shipment and dispensing of study 
treatment according to local institutional drug accountability processes. Full drug accountability for 
IMCgp100 is required in accordance with the International Conference on Harmonisation (ICH) Good 
Clinical Practice guidelines. Drug accountability will be noted by the field monitor during site visits and at 
the completion of the study. At study close-out, and, as appropriate during the course of the study, the 
investigator will return all used and unused study treatment, packaging, drug labels, and a copy of the 


 
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completed drug accountability logs to the site study monitor. Additional details including receipt of study 
products, storage and management of temperature excursions are provided in the study Pharmacy 
Manual.  
 Drug Supply, Storage, and Disposal 
Study treatments must be received by designated personnel at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the investigator and designated site personnel 
have access. Upon receipt, IMCgp100 supply should be recorded and stored according to the instructions 
specified on the drug labels. 
All IMCgp100 supply remaining at the end of the study, following appropriate drug accountability 
procedures at each site, can be destroyed per local institutional practice at the study site or at a third 
party vendor as appropriate and agreed to with Sponsor. All destruction of study medications must be 
documented appropriately.  
 
Management and Follow-up of Toxicity 
Patients whose treatment is interrupted or permanently discontinued due to an AE or clinically significant 
laboratory value, must be followed-up at least once a week (or more if clinically indicated) for 4 weeks, 
and subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed necessary for any AEs 
observed in the course of the trial. In the case of a toxicity suspected to be related to a cytokine release 
syndrome, the immunologic assessments outlined in Section 7.3.7.7 should be performed. In case of a 
worsening rash or other related skin toxicity (e.g., pruritus), a skin punch biopsy, as outlined in 
Section 7.3.7.10, should be considered.  
Guidelines for management of AE and dose modifications are presented below in Table 6-5 (below). 
Institutional protocols for management of immune-related AE should be implemented in cases of 
immune-related AE and will take precedence over guidance in Table 6-5. All patients must be followed up 
for the occurrence of AE and SAE for 90 days following the last dose of IMCgp100.  If more than 3 
consecutive doses of single-agent IMCgp100 are not administered due to drug-related toxicities or if a 
treatment gap occurs of greater than 21 days, the default position is that then the patient must be 
discontinued from the study. However, if a patient who misses more than 2 consecutive doses due to a 
drug-related toxicity is experiencing clinical benefit, and in the opinion of the investigator it is in the 
patient’s best interest to remain on study, then the patient may restart treatment after discussion with 
the Sponsor. 
 Hypotension 
Cases of severe hypotension have been observed across the IMCgp100 clinical trials. Initial therapy for 
low-grade hypotension is aggressive IV fluid (crystalloid or colloid) therapy. In cases of hypotension, where 
blood pressures are not immediately responding to fluid management, IV corticosteroid therapy should 
be considered. Cases of hypotension not complicated by additional symptoms associated with cytokine 


 
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release syndrome (CRS) (e.g., nausea, vomiting, malaise, and fever) have been observed with IMCgp100. 
Retrospective analyses of peripheral cytokines in the IMCgp100-102 study have suggested that mild-to-
moderate elevations in IL-6 after the first dose of IMCgp100 may be associated with more severe 
presentations of hypotension. Intervention with early IV corticosteroid in cases of hypotension without 
initial response to fluid therapy is warranted as described in Table 6-5. 
 Cytokine Release Syndrome 
Cases of CRS have been observed across the IMCgp100 clinical trials (as of 12 August 2018, CRS cases have 
been seen in 6% of patients in the current study overall,  and 2 of these cases were ≥ Grade 3). The pattern 
of CRS generally begins 2–12 hours following the first 3 doses of IMCgp100 and the observed toxicities 
include hypotension (which has been severe in some patients), rash or general erythema, pruritus, facial 
and general edema, pyrexia and chills. Other commonly reported symptoms, typically mild to moderate, 
include headache, fatigue, nausea, and vomiting. Grading of CRS is based on the modified grading system 
(Table 6-5). Aggressive management in cases of suspected CRS is warranted per guidance in Table 6-5. 
Early intervention with immunosuppression therapy (e.g., high-dose corticosteroid therapy) is warranted 
in cases of suspected CRS. 
Table 6-4 describes updated grading for events of CRS. 
Grade 
Symptoms 
1 
Symptoms are not life-threatening and require symptomatic treatment only (e.g., 
fever, nausea, fatigue, headache, myalgia, and malaise) 
2 
Symptoms require and respond to moderate intervention: 
 
Oxygen requirement < 40% 
 
Hypotension responsive to fluids or 1 low-dose vasopressor 
 
Grade 2 organ toxicity 
3 
Symptoms require and respond to aggressive intervention 
 
Oxygen requirement > 40% 
 
Hypotension requiring high-dose or multiple vasopressors 
 
Grade 3 organ toxicity 
 
Grade 4 transaminitis 
4 
Life-threatening symptoms 
 
Requirement for ventilator support 
 
Grade 4 organ toxicity (excluding transaminitis) 
5 
Death 
a. Lee 2014. 
 
 
 
Table 6-4 
Cytokine Release Syndrome Grading Scalea 


 
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Worst Toxicity NCI 
CTCAE v4.03 Grade 
Recommended Management and Dose Modifications 
Skin Toxicity 
Pruritus  
Grade 1  
Continue dosing. If symptomatic, consider systemic antihistamine regimen (see 
grade 2 guidance below).   
Grade 2  
Treat according to institutional practice and/or implement guidance below. Use 
systemic management and/or local skin management as indicated by symptoms.
Anti-pruritic regimen:   
1. Systemic 
antihistamine 
regimen 
recommended 
as 
first-line 
management of pruritus. Non-sedating, long-acting antihistamine 
(cetirizine, 10 mg oral or equivalent). If a sedating antihistamine is 
preferred (e.g., evening dosing) consider diphenhydramine 25 mg oral 
or intravenous. The use of sedating anti-histamines should be minimized 
in patients with co-morbid pulmonary pathology including pulmonary 
metastases or underlying inflammatory airways disease such as chronic 
obstructive pulmonary disease or asthma  
2. Topical corticosteroid regimens 
Preparation of recommended regimens: 
 
For face and/or intertriginous areas (including genitalia) recommend 
alclometasone 0.05% or hydrocortisone 2.5% creams  
 
For other body areas (i.e., trunk and extremities), recommend 
clobetasol or betamethasone 0.05% creams. Consider spray 
preparation for ease of application on trunk. For scalp involvement, 
consider a foam preparation  
Prophylaxis for subsequent doses is generally not required after grade 2 
pruritus, but a non-sedating anti-histamine may be considered.  
Grade 3  
Hold all doses of IMCgp100 until returned to NCI CTCAE grade ≤ 1.  
Manage pruritus according to institutional protocol and guidance below.  
Management:   
Treat according to institutional practice which generally includes an anti-pruritic 
regimen (see grade 2 management above). In addition, corticosteroid treatment 
(oral or intravenous) can be considered for pruritus that does not respond to 
antihistamine therapy (recommend oral prednisone 20–40 mg or a single dose 
of 25 mg hydrocortisone intravenous or the equivalent for refractory pruritus). 
For recommended systemic or topical regimens, refer to grade 2 management 
above).   
Prophylaxis:   
In patients experiencing grade 3 pruritus, administration of a non-sedating 
antihistamine prophylaxis dose is recommended for the subsequent dose of 
IMCgp100, approximately 1–2 hours prior to the IMCgp100 dose being 
administered (e.g., cetirizine 10 mg or equivalent).  
Prophylaxis with corticosteroid can be considered if pruritus recurs at a similar 
or worse severity despite antihistamine prophylaxis (recommend oral 
Table 6-5 
Recommended Management and Dose Modifications of IMCgp100 by Toxicity 
Grade for Study Medications 


 
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Worst Toxicity NCI 
CTCAE v4.03 Grade 
Recommended Management and Dose Modifications 
prednisone 20–40 mg or a single dose of 25 mg hydrocortisone intravenous or 
the equivalent). If steroid prophylaxis is used, the steroid dose should be titrated 
to the minimum effective dose and ultimately discontinued if possible. 
Rash/Photosensitivity 
Grade 1 
Continue dosing. If symptomatic, consider systemic antihistamine regimen 
according to management guidance for pruritus (above).  
Grade 2 
Hold all doses of study IMCgp100 until returned to NCI CTCAE grade ≤1. 
Use local skin management and systemic antihistamine regimen as indicated for 
symptoms. With observation of bullous formation or blistering rashes, consider 
dermatology consultation to rule out other causes (e.g., bullous pemphigoid). Oral 
or topical corticosteroids can be used for bullous formations or blistering. If bullous 
formation or blistering recur, consult Sponsor Medical Monitor for guidance.  
Antihistamine (anti-pruritic) regimen:   
1. Systemic antihistamine regimen recommended as first line management 
of pruritus.  
 Non-sedating, long acting antihistamine (cetirizine, 10 mg oral or 
equivalent). If a sedating antihistamine is preferred (e.g., evening dosing) 
consider diphenhydramine 25 mg oral or intravenous. The use of sedating 
anti-histamines should be minimized in patients with co-morbid pulmonary 
pathology including pulmonary metastases or underlying inflammatory 
airway disease such as chronic obstructive pulmonary disease or asthma 
 Use of oral corticosteroid dosing for shorter time frames (e.g., 3 days or 
fewer) may not require tapering dosing 
2. Topical corticosteroid regimens  
Preparation of recommended regimens:    
 For face and/or intertriginous areas (including genitalia) recommend 
alclometasone 0.05% or hydrocortisone 2.5% creams  
 For other body areas (i.e., trunk and extremities), recommend clobetasol or 
betamethasone 0.05% creams. Consider spray preparation for ease of 
application on trunk. For scalp involvement, consider a foam preparation  
Grade 3 
Hold all doses of IMCgp100 until returned to NCI CTCAE grade ≤ 1. 
Management:   
Treat according to institutional practice which generally includes an anti-pruritic 
regimen (see grade 2 management above). In addition, corticosteroid treatment 
(oral or topical) can be considered for symptomatic rash that does not respond to 
anti-pruritic regimen. For topical regimens, refer to grade 2 management above.  
Oral or topical corticosteroids can be used for bullous formations or blistering. If 
bullous formation or blistering recur, consult Sponsor Medical Monitor for 
guidance. 


 
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Dose adjustments: 
If grade 3 rash observed with IMCg100 resolves to NCI CTCAE grade ≤ 1 within 
7 days, restart at the same dose level. If grade 3 rash resolves to NCI CTCAE 
grade ≤ 1 in 7–21 days, restart with 1 dose-level reduction in IMCgp1001. 
Grade 4 
Any grade 4 rash regardless of presentation, permanently discontinue IMCgp100. 
Manage according to institutional practice, consultation with a dermatologist is 
recommended.  
Hypotension 
Mild, 
asymptomatic  
decrease2:  e.g., < 
15 mmHg systolic 
blood pressure 
Grade 1 
Increase frequency of vital sign assessments to every 2 hours. 
Consider maintenance intravenous fluids if mild decrease in blood pressure (e.g., 
systolic blood pressure < 110 mmHg or decrease in SBP of approximately less 
than 15 mmHg). 
 
Admit for inpatient monitoring (unless already hospitalized per protocol). 
Consider associated symptoms present and consider diagnosis of cytokine 
release syndrome (see below) 
 
Administer bolus intravenous fluids at a rate of approximately 1 L crystalloid 
per hour. If hypotension does not resolve with intravenous fluid therapy, 
consider intravenous corticosteroid therapy (e.g., methylprednisolone 2 
mg/kg initial dose or equivalent) 
Consider prophylactic electrolyte supplementation for patients receiving 
intravenous fluids with low-normal serum phosphorus or magnesium electrolyte 
levels. 
Moderate, 
asymptomatic 
decrease2:  e.g., 
≥ 15 mmHg, but 
< 35 mmHg 
systolic blood 
pressure 
Grade 2 
Increase frequency of vitals to every 1 to 2 hours, or more frequently as medically 
necessary. 
Monitor fluid balance status with careful attention to clinical volume status, as 
assessed by degree of peripheral edema or rales on pulmonary examination. 
Administer bolus intravenous fluids at a rate of approximately 1 L crystalloid per 
hour. If the patient is asymptomatic and non-orthostatic after infusion of 2-3 L 
administered over 2–3 hours, consider transition to maintenance intravenous 
fluids until resolved. 
If hypotension is not rapidly resolved with intravenous crystalloid therapy, add 
intravenous corticosteroid therapy of methylprednisolone 2 mg/kg initial dose or 
equivalent 
Consider prophylactic electrolyte supplementation for patients receiving 
intravenous fluids with low-normal serum electrolyte levels. 
Moderate, 
symptomatic 
decrease2:  e.g., 
≥ 15 mmHg and 
orthostasis 
Grade 3 
Increase frequency of vitals to every 1 hour, or more frequently as medically 
necessary. 
Administer bolus intravenous fluids at a rate of approximately 1 L crystalloid per 
hour. If the patient has symptomatic orthostatic hypotension after infusion of 2–3 
L administered over 2–3 hours, consider administration of corticosteroids such as 
intravenous methylprednisolone 2 mg/kg or equivalent. 
Initiate vasopressor therapy as required to maintain blood pressure.  


 
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Consider prophylactic electrolyte supplementation for patients receiving 
intravenous fluids with low-normal serum electrolyte levels. 
If appropriate, consider additional measures according to the institutional 
cytokine release protocol (also see management of Infusion-related Reactions 
below). 
If resolved within 48 hours of onset, no change in dosing is necessary. If repeat 
hypotension occurs, consult with the Sponsor Medical Monitor prior to 
subsequent dosing. Please refer to guidance for continued inpatient monitoring to 
determine need for continued inpatient monitoring (Section 6.2). 
Consider the diagnosis of cytokine release syndrome and management (below). 
Severe, 
symptomatic 
decrease2:  e.g., 
≥ 35 mmHg 
systolic and 
symptomatic when 
supine or mean 
arterial pressure3 ≤ 
55 mmHg 
Grade 4 
Immediately administer high-dose intravenous corticosteroid therapy of 
methylprednisolone 2 mg/kg initial dose or equivalent. Maximize vasopressor 
therapy and fluid management. Administer bolus intravenous fluids (1 L 
crystalloid as rapidly as feasible) and consider escalation to higher level of care 
i.e., intensive care unit). 
Consider maximal immunosuppression with high-dose intravenous corticosteroid 
therapy and consider additional measures (e.g., anti-IL6, tocilizumab) as 
required. 
If appropriate, aggressive fluid therapy as indicated and described above; 
consider additional measures according to prophylactic electrolyte 
supplementation for patients receiving intravenous fluids with low-normal serum 
electrolyte levels. 
Monitor vital signs every hour until resolved. 
Consider additional measures according to the institutional cytokine release 
protocol (also see management of Infusion-related Reactions / Cytokine Release 
Syndrome below). 
IMCgp100 must be dose reduced or discontinued. The Sponsor Medical Monitor 
should be consulted for discussion of individual case management. 
Infusion-related Reactions/Anaphylaxis (occurring during infusion) 
Grade 1 
Administer medications for symptomatic relief as needed. Infusion interruption may 
be considered until resolution of the event (up to 4 hours). The infusion rate of the 
study medication may be decreased by 50%. If resolved with decreased rate of 
infusion, any subsequent infusions can be administered at the reduced rate.  
Grade 2 
Stop infusion and keep intravenous line open. Treat according to institutional 
practice. Provide all supportive measures as indicated. Provide supplemental 
oxygen and fluids, as needed.  
Monitor vital signs (e.g., blood pressure, pulse, and temperature) until resolution. 
Administer medications for symptomatic relief as needed. Antihistamines, 
acetaminophen (paracetamol), or corticosteroids may be administered, as needed 
at the discretion of the investigator. 


 
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Restart infusion only once infusion reaction resolves (within 4 hours of initial start 
of infusion), ensuring there is minimum observation period of one hour from stop 
of initial infusion to restart at reduced rate. Administer oral pre-medication (e.g., 
1000 mg of acetaminophen or paracetamol, 50–100 mg diphenhydramine 
hydrochloride or alternative antihistamine), 60 minutes prior to restarting the 
infusion, accounting for prior doses/time given for management of initial reaction. 
Restart infusion at 50% of previous rate under continuous observation. If the 
adverse event recurs at the reinitiated slow rate of infusion, and despite oral pre-
medication, then permanently discontinue the patient from study treatment. 
Grade 3 or 4 
Discontinue infusion immediately, and permanently discontinue patient from study 
treatment. Grade 3 infusion-related reactions that improve by at least 1 grade 
within 6 hours of onset with medical management will not require permanent 
discontinuation. If treatment is continued all guidance provided for the 
management of grade 2 reactions must be followed.  
Manage severe infusion-related reactions per institutional standards. Provide 
supplemental oxygen, fluids, and other resuscitative measures as needed. Monitor 
vital signs (e.g., blood pressure, pulse, respiration, and temperature) until 
resolution. 
Infusion-related Reactions/Cytokine Release Syndrome — refer to modified grading system 
provided in Table 6-4 
Grade 1 
Symptoms are not life-threatening and require symptomatic treatment only (e.g., 
fever, nausea, fatigue, headache, myalgia, and malaise) 
 
Admit for inpatient monitoring (unless already hospitalized per protocols) and 
manage according to individual symptoms. Assess for potential infection and 
treat fever and neutropenia. Initiate bolus and/or maintenance intravenous 
fluids and carefully monitor fluid balance 
 
Consider prophylactic electrolyte supplementation for patients receiving 
intravenous fluids with low-normal serum electrolyte levels 
 
Vigilantly monitor for escalation to grade 2 cytokine release syndrome with 
frequent vital signs (e.g., every-hour vital signs). Strongly consider early, high-
dose corticosteroid therapy with changes in vital signs (see grade 2 below) 
Grade 2  
 
Symptoms are moderate and require medical management. Management as 
above (grade 1) and include the following measures: 
 
Increase monitoring with continuous cardiac and pulse oximetry monitoring 
and continue or increase vital sign monitoring (e.g., every hour vital signs) 
 
To manage hypotension, administer bolus intravenous fluids (recommended 
rate of approximately 1 L per hour). If not rapidly resolved with fluids, high-
dose intravenous corticosteroid therapy should be considered, e.g., 
methylprednisolone 2 mg/kg initial dose (or equivalent) until symptoms (e.g., 
hypotension) resolve 
 
Consider prophylactic electrolyte supplementation for patients receiving 
intravenous fluids with low-normal serum electrolyte levels 
 
Manage respiratory distress and oxygen requirement with supplemental 
oxygen and additional respiratory support as needed 


 
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Grade 3 
 
Symptoms are severe and require enhanced management. Management as above 
(grade 2) and include the following measures: 
 
Maximize immunosuppression with continued high-dose intravenous 
corticosteroid (e.g., methylprednisolone 2 mg/kg/day or equivalent). Consider 
adding further immunosuppression measures or additional interventions 
according to the institutional cytokine release protocol (e.g., anti-IL6, 
tocilizumab) 
 
Continue to manage symptoms and vigilantly monitor for escalation 
Patient may restart IMCgp100 if symptoms resolve and only after discussion and 
written approval of Sponsor Medical Monitor.  
Grade 4 
Symptoms are severe and organ toxicity observed. Management as above (grade 
3) and include the following measures.  
 
Additional immunosuppression recommended (e.g., anti-IL6, tocilizumab) 
with continued high-dose intravenous corticosteroid therapy as described 
above (e.g., methylprednisolone 2 mg/kg/day or equivalent) 
 
If appropriate, consider additional measures according to the institutional 
cytokine release protocol   
Permanently discontinue all study medications.  
Hepatic Function Abnormalities 
Grade 2 
Regular monitoring of liver function tests until improving or resolved. Evaluate 
concurrent medications for agents that may prolong or exacerbate laboratory 
abnormalities. Consider intravenous corticosteroid therapy (e.g., hydrocortisone 
100 mg or the equivalent) if not improving within 72 hours. 
Grade 3 
Hold all doses of IMCgp100 until returned to NCI CTCAE grade ≤ 1. Regular 
monitoring of liver function tests until improving or resolved. Consider intravenous 
corticosteroid therapy (e.g., hydrocortisone 100 mg or the equivalent).  
Dosing may resume after discussion with the Sponsor Medical Monitor once all 
laboratory abnormalities returned to NCI CTCAE grade ≤ 1.  
Grade 4 
Hold all doses of IMCgp100 until returned to NCI CTCAE grade ≤ 1. Regular 
monitoring of liver function tests until improving or resolved. Promptly consider 
intravenous corticosteroid therapy (e.g., hydrocortisone 100 mg or the equivalent) 
if not resolving within 24 hours. Consider hepatology consult and additional 
abdominal imaging. 
Dosing may resume after discussion with the Sponsor Medical Monitor and once 
all laboratory abnormalities returned to NCI CTCAE grade ≤ 1. 
Vomiting 
Grade 2 
Anti-emetic therapy as per institutional standard. Intravenous fluid support and 
other supportive measures for additional adverse events as needed.  
Grade 3 or 4 
Consider holding all doses of IMCgp100 until returned to NCI CTCAE grade ≤ 1. 
Anti-emetic therapy as per institutional standard. Intravenous fluid support and 
other supportive measures for additional adverse events.  


 
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Other Adverse Events 
In patients experiencing adverse events (not meeting the specific criteria above) of grade > 3, study 
drugs should be omitted until resolved to grade < 1, unless discussed and agreed with Sponsor Medical 
Monitor.  
Treat according to institutional practice and for immune-related adverse event of grade ≥ 3, treatment 
with corticosteroids should be considered. Consult Sponsor Medical Monitor for further guidance as 
needed. 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
1. Dose reductions of IMCgp100 for toxicity is as follows:  from a starting dose IMCgp100 dose of 68 
mcg, the dose will be reduced to 54 mcg for any toxicity requiring dose reduction. The dose may be 
reduced further to 50 mcg for recurrent toxicity. Patients who require more than 2 dose reductions of 
IMCgp100 should discontinue treatment. All dose modifications should be based on the worst preceding 
toxicity. Once a dose has been reduced it may be increased to the initial dose level if there is no 
recurrence of toxicity with subsequent doses of IMCgp100. 
2. The absolute systolic blood pressure change is provided as guidance for management, and must be 
interpreted in the clinical context of the patient. Patients with baseline hypertension may not require 
intervention for mild or moderate decreases in systolic blood pressure. 
3. Mean arterial pressure = 1/3 (systolic blood pressure – diastolic blood pressure) + diastolic blood 
pressure.  
 Treatment Discontinuation  
Reasons for discontinuation of study treatment will include: 
 
Unequivocal, confirmed disease progression referring to the modified irRECIST criteria  
(Wolchok, 2009; Nishino, 2013; Bohnsack, 2014; refer to Section 6.10.1 and Appendix 1) 
 
Initiation of alternative anti-cancer therapy including another investigational agent 
 
Unacceptable toxicity defined as an AE that, in the opinion of the investigator or the Sponsor, 
contraindicates further dosing 
 
Withdrawal of consent from further treatment with investigational product by the patient or the 
investigator or lost to follow-up  
 
Patient is determined to have met 1 or more of the exclusion criteria or failed to meet all of the 
inclusion criteria for study participation AND continuing to receive investigational product might 
constitute a safety risk. Patients who fall into this category and for whom continuation of 
treatment is not thought to pose a safety risk in the opinion of the investigator may continue to 
receive study treatment after discussion with the Sponsor Medical Monitor  
 
Pregnancy or intent to become pregnant  


 
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At the time patients discontinue study treatment, the EOT visit should be scheduled as soon as possible 
and in the appropriate window of 14 days after the last dose was administered. At this visit, all of the 
assessments listed for the EOT visit will be performed (see Table 7-1). If the decision to withdraw the 
patient occurs at a regularly scheduled visit, that visit may become the EOT visit rather than having the 
patient return for an additional visit (safety follow-up will still continue for the full 90-day observation 
period, see Section 7.2 for details of assessments required at EOT). An End of Treatment Phase Disposition 
eCRF page should be completed at the EOT visit, giving the date and reason for stopping the study 
treatment. End of treatment/premature withdrawal visit is not considered as the end of the study. 
Patients should still be followed for survival information and, if the patient does not have PD, imaging 
data should continue to be collected to capture progression based on RECISTv.1.1. 
Patients who discontinue study treatment should NOT be considered withdrawn from the study as they 
will be followed for the OS endpoint. They should return for the assessments indicated in Section 7 and 
Table 7-1. If they fail to return for these assessments for unknown reasons, every effort (e.g., telephone, 
email, and registered letter) should be made to contact them. If a patient discontinues study treatment, 
but continues study assessments, the patient remains on study until such time as he/she completes 
protocol criteria for ending study assessments. At that time, the reason for study completion should be 
recorded on the Study Disposition eCRF page. 
 Criteria for Treatment Beyond Initial RECIST v.1.1 Disease Progression  
For patients in the study, if PD based on RECIST v.1.1 occurs, and the patient does NOT have clinical 
symptomatic progression that would require a change in therapy to adequately manage symptoms, the 
patient will be considered to continue in disease control (immune-related stable disease) and may consent 
to continue to be treated according to the protocol-specified regimens until 1 of the following criteria is 
met: 
1. Unequivocal, confirmed irPD based on modified irRECIST (guidelines based on Wolchok, 2009; 
Nishino, 2013, Bohnsack, 2014):  An initial assessment of PD by RECIST v.1.1 (initial PD 
assessment) will be confirmed with a repeat radiologic evaluation performed at least 4 weeks 
later as scheduled per protocol. For patients who continue IMCgp100 therapy beyond initial PD 
per RECISTv1.1, unequivocal, confirmed irPD is defined as an additional 20% increase or greater 
in tumor burden (sum of diameters of both target and measurable new lesions) or unequivocal 
progression of NTLs and/or new non-measurable disease from the initial PD assessment per 
RECISTv1.1 
2. Meets any of the investigational product discontinuation criteria (Section 6.10) 
3. Clinical symptoms or signs indicating clinically significant PD (not meeting radiologic PD) such as 
the benefit-risk ratio of continuing therapy is no longer justified 


 
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4. Rapid PD or threat to vital organs/critical anatomical sites (e.g., spinal cord compression) requiring 
urgent alternative medical intervention, and/or continuation of study therapy would prevent 
institution of such intervention 
Patients continuing treatment beyond the protocol-specified RECIST v.1.1 progression will continue to 
follow the treatment regimen of QW IMCgp100. Imaging data will continue to be collected until confirmed 
immune-related progression (irPD) based on modified irRECIST. 
 Study Discontinuation   
Reasons for individual patients discontinuing from study include: 
 
Patient dies 
 
Patient is lost to follow-up 
 
Patient withdraws consent for any further participation including further survival follow-up 
 
The end of study is reached (please refer to Section 3.5 and Section 3.6) 


 
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7 STUDY SCHEDULE AND ASSESSMENTS 
 
Screening Procedures and Assessments 
All of the assessments required as part of the study are indicated in Table 7-1 organized by visit date, with 
assessments required indicated with an “X” at the specific visits when they should be performed. All 
assessments listed as “Screening” must be performed within 21 days before C1D1. The only exception to 
the Screening Period of 21 days are the baseline radiological evaluations which must be performed within 
28 days of the screening visit. Assessments required on C1D1 that are performed as part of the screening 
evaluations and within 72 hours prior to the first dose of study treatment, do not need to be repeated on 
C1D1. Laboratory assessments required on subsequent dosing days may be performed 1 day prior to 
IMCgp100 administration. Laboratory and radiological assessments performed as part of standard of care 
prior to signing informed consent may be used if performed within the screening time window (21 days 
for laboratory assessments and 28 days for radiological assessments). 
During the course of the study visits, test and/or procedures should occur on schedule whenever possible. 
A visit window of ± 7 days is allowed unless otherwise indicated in the protocol. If the study drug infusions 
are delayed, the assessments will be moved with the delayed study drug infusions. The only exception to 
moving study assessments with treatment are the radiological assessments, which must be performed ± 
7 days of the scheduled date of the assessment (unless otherwise indicated in the protocol). The protocol 
specified radiologic assessments should be performed as scheduled every 8 or 12 weeks as indicated in 
the protocol, using as reference to C1D1 and should not follow delays incurred in the treatment period. 
Radiologic assessments should not move if delays in treatment are incurred.  


 
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Screening 
Phase 
Treatment Phase 
Follow-up Phase 
Procedure 
Protocol 
Section 
Screening 
Cycle 1 
Cycle 2 
Cycle 3a 
Later 
Cyclesa 
EOT 
90-day 
Safety 
Follow 
Up 
Disease 
Progression 
Follow Up 
Survival 
Follow 
Upb 
Day of Cycle 
 
-21 to -1 
1 
2 
8 
9 
15 
16 
22 
1 
8 
15 
22 
1 
8 
1
5 
2
2 
1-28 
 
 
 
 
Informed consent 
7.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
7.1.1.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
5.2 / 5.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
7.1.1.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and 
extent of cancer 
7.1.1.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior anti-cancer 
therapy 
6.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
6.5 
X 
Continuously assessed 
 
 
Physical 
examinationc 
7.3.3 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Height  
7.3.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
7.3.5 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Vital signsd 
7.3.4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG 
performance 
statuse 
7.3.6 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Hematology panelf 
7.3.7.1 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Chemistry panelg 
7.3.7.2 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Inflammatory 
Analytesh 
7.3.7.3 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
7.3.7.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis 
7.3.7.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Table 7-1 
Schedule of Study Assessments 


 
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Screening 
Phase 
Treatment Phase 
Follow-up Phase 
Procedure 
Protocol 
Section 
Screening 
Cycle 1 
Cycle 2 
Cycle 3a 
Later 
Cyclesa 
EOT 
90-day 
Safety 
Follow 
Up 
Disease 
Progression 
Follow Up 
Survival 
Follow 
Upb 
Day of Cycle 
 
-21 to -1 
1 
2 
8 
9 
15 
16 
22 
1 
8 
15 
22 
1 
8 
1
5 
2
2 
1-28 
 
 
 
 
Thyroid function 
7.3.7.6 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Skin punch biopsy 
(optional)j 
7.3.7.10 
 
 
 
 
 
In case of increased skin toxicity in any patient at C1D15 or thereafter (optional) 
 
 
 
Pregnancy testk 
7.3.7.8 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Anti-neoplastic 
therapies since 
discontinuation of 
study treatment 
7.2.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
Tumor evaluation 
as per RECIST 
v.1.1 and as per 
irRECISTm 
7.3.1 
Table 7-2 
X 
Every 8 weeks from C1D1 to C11D1 (40 weeks), then every 12 weeks until confirmed PD per RECISTv1.1. Note, for patients who continue 
treatment beyond progression per RECISTv.1.1, imaging should continue while on treatment until disease progression per modified irRECIST. 
At EOT, if a scan was not conducted within 30 days prior to EOT. Note, if a patient discontinues treatment, but remains in Disease Progression 
Follow Up, then imaging visits should continue as per the original study plan and will not be needed at the EOT visit. 
 
12-lead ECG 
7.3.7.9 
Table 7-6 
X 
Refer to ECG schedule Table 7-6 
 
 
 
Adverse events 
8 
 
Continuously assessed 
 
 


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Screening 
Phase 
Treatment Phase 
Follow-up Phase 
Procedure 
Protocol 
Section 
Screening 
Cycle 1 
Cycle 2 
Cycle 3a 
Later 
Cyclesa 
EOT 
90-day 
Safety 
Follow 
Up 
Disease 
Progression 
Follow Up 
Survival 
Follow 
Upb 
Day of Cycle 
-21 to -1 
1 
2 
8 
9 
15 
16 
22 
1 
8 
15 
22 
1 
8 
1
5 
2
2 
1-28 
IMCgp100 
administrationq 
6.1.1 
IMCgp100 given intravenously every week with C1D15 intra-patient escalation
PK samplingr 
7.3.8  
Table 7-7 
PK sampling to be scheduled according to Table 7-7 
Immunogenicity 
samplingr 
7.3.8 
Table 7-7
See Table 7-7 for immunogenicity sampling timing 
HLA-A2 
determinations 
7.1.1.3 
X 
 
 
 
 
 
 
 
 
 
 
Survival contact for 
follow-up 
7.2.5 
X 
C#D# = Cycle # Day #; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; HLA-A2 = human leukocyte 
antigen-A2; IFN-γ = interferon gamma; IL-6 = interleukin-6; irRECIST = immune-related response criteria; PD = progressive disease; PK = pharmacokinetic; 
 
 RECIST = Response Evaluation Criteria in Solid Tumors. 
FOOTNOTES: 
a  Cycles 4 and greater will follow the same schedule of assessments as outlined for Cycle 3 with exception of tumor imaging which will follow the noted schedule and PK and 
pharmacodynamic assessments which will follow the schedules in Table 7-7 and Table 7-8, respectively.  
b  Patients might be contacted earlier than the 3 month time point for survival follow-up during the interim and final analysis 
c  Physical Examination should be done prior to administration of IMCgp100 and from C1D8 onwards, a short physical examination will be performed 
d  Overnight inpatient hospitalization and frequent vital signs (minimum of pre-dose and Q4 hours vital signs) are required at C1D1, C1D8, and C1D15. Inpatient monitoring at C1D22 
will be determined based on the toxicity profile in the individual patient at C1D15. Patients experiencing a grade 2 or greater hypotension event at C1D15 must be observed as an 
inpatient for the subsequent C1D22 dose. Patients experiencing a grade 3 or 4 hypotension event during the inpatient monitoring at C1D1, C1D8, or C1D15 will require additional 
monitoring for any doses administered as an outpatient through C2D15. If patients have experienced grade 3 or 4 hypotension at any of these doses, then outpatient monitoring 
through C2D15 must be for a minimum of 8 hours after the IMCgp100 dose with vital signs monitored every hour. Please refer to Section 6.2 weekly and Section 7.3.4 for details of 
overnight hospitalizations and vital signs monitoring. 
e  ECOG Performance Status will be determined on Day 1 of every odd-numbered cycle and at EOT. 


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f  Hematology panel should be obtained at Screening and before every dose of IMCgp100. In addition, the hematology panel is obtained the day following the first and third doses, on 
C1D2 and C1D16. Hematology panel is performed at EOT visit as well. 
g  Chemistry panel should be obtained at Screening and before every dose of IMCgp100 and at EOT. 
  
 
 
j  Skin punch biopsy should be obtained in patients with worsened rash on C1D15 or beyond as compared to the rash experienced on IMCgp100 dosing days on C1D1 or C1D8. This 
skin biopsy is optional. 
k  Pregnancy testing is required only in all females with childbearing potential. At Screening, a serum pregnancy test must be performed within 72 hours before the first dose. During the 
study (Day 1 of each cycle starting with Cycle 2) a serum or urine pregnancy test must be performed. At EOT, a serum or urine pregnancy test must also be performed. 
  
  
m  Radiologic assessments should be performed as scheduled every 8 weeks from C1D1 to Week 40 (C11D1), then every 12 weeks until confirmed PD per RECISTv.1.1 (See 
Table 7-2), using as reference to C1D1 and should NOT follow delays incurred in the treatment period. Radiologic assessments at each timepoint are listed in Table 7-2. Partial 
response, minor response, and complete response, per both RECIST v.1.1 and modified irRECIST, should be confirmed by a new assessment after at least 4 weeks.  
n  Dose escalation cohorts:  Submission of an archival tumor sample from each patient is required. In the absence of an archival tumor biopsy, a newly obtained tumor biopsy can be 
obtained. If the new tumor biopsy cannot be obtained or is not medically feasible this should be discussed with the Sponsor Medical Monitor prior to enrollment. Dose expansion 
cohorts:  Submission of an archival tumor sample is requested, if available. 
o Dose escalation cohorts:  Collection of a tumor sample at Screening is mandatory, unless the tissue sample can be obtained from an archival tumor sample (see Table 7-8). On-
treatment C1D2 and/or C1D16 biopsy is optional in all dose escalation cohorts. Dose expansion cohorts:  Fresh tumor biopsy at Screening is MANDATORY. If the new tumor 
biopsy is not medically feasible, this must be discussed with the Sponsor Medical Monitor prior to enrollment. One on-treatment biopsy is mandatory in the expansion cohorts unless 
medically not feasible. See Section 7.4.3. Only non-significant risk procedures should be performed for accessing tumor tissue in patients enrolled in the trial.  
p  A biopsy obtained at the time of disease progression in the setting of treatment resistance is optional in the EOT or follow-up period for both the dose escalation and dose expansion 
cohorts.  
q  Please refer to Section 6.1 Study Treatment for details of weekly IMCgp100 administration and intra-patient dose escalation regimen (at C1D15; Section 6.2) used in this study. 
t  PK sampling should follow the PK and immunogenicity sampling table (Table 7-7).  
s  For all patients, HLA-A2 status will be determined via central assay during Pre-screening. Patients should not sign the Main Study ICF and enter Screening until the result of the central 
assay in Pre-Screening is known as HLA-A*0201 positive. Patients who re-screen for the trial need not return to the pre-screen period once HLA results are known. 
 
 
 


 
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 Screening Assessments 
The study IRB/IEC-approved ICF must be signed and dated before any screening procedures are 
performed, except for laboratory and radiological evaluations performed as part of standard of care 
within the screening window (28 days for radiological assessments, 21 days for all other assessments). 
Patients will be evaluated against study inclusion and exclusion criteria and safety assessments 
required at Baseline will be performed. For details of all screening assessments, refer to Table 7-1. 
Screening assessments must be repeated if performed outside of the specified screening window. 
Patients may re-screen after abnormal labs or symptoms are corrected or treated after consultation 
with the Sponsor. 
Radiologic assessments required at screening include CT or MRI of the chest, abdomen, and pelvis. 
Brain MRI is required at Screening only if there is clinical suspicion of brain metastasis at Screening.  
7.1.1.1 Information to be Collected on Screening Failures 
A patient who signed the Main Study ICF, but failed to be started on treatment for any reason will be 
considered a screen failure. If patients are found not eligible after signing the main study consent, the 
patients will be considered as screening failures, and data will be handled in the same manner. 
The demographic information, informed consent, and screening pages (with reason for screen fail) 
must also be completed for screen failure patients. No other data will be entered into the clinical 
database for patients who are screen failures, unless the patient experienced a SAE during Screening, 
which would be reported in the usual manner via eCRF AE page (See Section 8.4). 
7.1.1.2 Patient Demographics and Other Baseline Characteristics 
Data to be collected will include general patient demographics, relevant medical history and current 
medical conditions, diagnosis and extent of cancer, details of prior anti-cancer treatments, 
prior/concomitant medications, prior procedures, significant non-drug therapies and any other 
assessments that are done for determining eligibility for inclusion in the study. Prior anti-neoplastic 
therapies including medications, radiotherapy, and surgery are to be recorded on the separate Prior 
Anti-neoplastic Therapy eCRF during Screening. 
7.1.1.3 HLA-A2 Status Determination  
For all patients, HLA-A2 status will be determined during Pre-screening by central assay. Patients 
should not sign the Main Study ICF and enter Screening until the results of the central assay in Pre-
screening is known as HLA-A*0201 positive. Patients who are known to be HLA-A*0201 positive from 
a prior assessment may complete the pre-screening and screening in parallel. A Pre-screening HLA 
sample should still be submitted for central analysis of HLA. Patients who re-screen for the trial need 
not return to the pre-screen period once HLA results are known. 


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Treatment, Treatment Discontinuation and Follow-up Phases 
 Treatment Period 
For the purposes of scheduling procedures and evaluations, a treatment cycle is defined as 4 weeks 
(28 days). Please refer to Table 7-1 for details of the timing of required assessments and visit windows. 
Patients will be treated until they experience unacceptable toxicity, PD per modified irRECIST and/or 
treatment is discontinued at the discretion of the investigator or the patient, as described in 
Section 6.10.1.  
Patients who have disease progression per RECIST v.1.1, but have evidence of clinical benefit, such as 
disease shrinkage at other sites or symptomatic improvement, may continue treatment after 
discussion with the Sponsor. Patients who consent to continue treatment after RECIST v.1.1 disease 
progression should discontinue study treatment once they are no longer deriving benefit as assessed 
by the investigator and as per guidance in Section 6.10.1.  
Patient reported outcomes (PRO) will be assessed before dosing on C1D1 and then throughout the 
treatment period using (1) the general health status EQ-5D, 5L questionnaires, and (2) the HRQoL 
instrument EORTC QLQ-C30. Details of PRO assessments are provided in Section 7.3.9.  
Discontinuation of Study Treatment and End of Treatment Visit 
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a patient 
decides to discontinue from the study treatment, the investigator should make every effort to 
determine the primary reason for this decision and record this information in the patient’s chart and 
on the appropriate eCRF pages. Other reasons for discontinuation of study treatment are outlined in 
Section 6.10.  
Patients will be considered withdrawn from therapy if they state an intention to withdraw, and fail to 
return for visits or become lost to follow-up for any other reason. 
The investigator should discontinue study treatment for a given patient if, on balance, he/she believes 
that continuation would be detrimental to the patient’s well-being. 
At the time patients discontinue study treatment, a visit should be scheduled as soon as possible, and 
within 14 days of the last dose of study drug or within 14 days of the decision to permanently 
discontinue study treatment, at which time all of the assessments listed for the EOT visit will be 
performed (Table 7-1). If the decision to withdraw the patient occurs at a regularly scheduled visit, 
that visit may become the EOT visit rather than having the patient return for an additional visit. An 
End of Treatment Phase Disposition eCRF page should be completed, giving the date and reason for 
stopping the study treatment. End of treatment/premature withdrawal visit is not considered as the 
end of the study. 
Patients who discontinue study treatment should NOT be considered withdrawn from the study. They 
should return for the assessments indicated in Section 7 and Table 7-1. If they fail to return for these 
assessments for unknown reasons, every effort (e.g., telephone, email, postal letter) should be made 
to contact them. If a patient discontinues study treatment, but continues study assessments, the 
patient remains on study until such time as he/she completes protocol criteria for ending study 


 
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assessments. At that time, the reason for study completion should be recorded on the Study 
Disposition eCRF page. 
 90-day Safety Follow-up Period 
All patients must have safety evaluations 90 days after the last dose of study treatment. Information 
related to all AEs (including concomitant medication taken for on-going AEs) will be collected for 90 
days after the last dose of study drug. All AEs suspected to be related to study treatment should be 
followed up weekly or as clinically indicated until resolution or stabilization. 
Anti-neoplastic therapies since discontinuation of study drug will be collected during this follow-up 
period. 
 Disease Progression Follow-up Period 
Patients who discontinue study treatment for any reason other than death, disease progression per 
RECIST v.1.1 , lost to follow-up, withdrawal of consent, or study termination, should return for tumor 
evaluation assessments every 8 weeks until 40 weeks, and then every 12 weeks until progression of 
disease per RECIST v.1.1.  
 
All patients who discontinue treatment for reasons other than PD per RECISTv1.1 will be 
followed with imaging until evidence of PD per RECISTv1.1 . 
 
For patients who consent to and continue treatment beyond progression per RECISTv1.1, 
imaging should continue until progression per modified irRECIST (irPD) or treatment 
discontinuation. 
 
If patients choose not to return for these visits or are unable to do so, every effort should be 
made to contact them or a knowledgeable informant by telephone to determine if the patient 
has had disease progression.   
 
Patients who discontinue treatment for reasons of disease progression by either RECISTv1.1 
or modified irRECIST criteria will not enter the Disease Progression Follow-up Period. 
 
Anti-neoplastic therapies since discontinuation of study drug will be collected during this 
follow-up period. 
See Table 7-2 for additional details on Disease Assessment Collection Plan. 
 Survival Follow-up Period 
Upon completion of the 90-day safety follow up or disease progression follow up, patients will be 
followed for survival every 12 weeks (can be done by telephone call) until death or until the end of 
the study is reached, unless they withdraw consent or are lost to follow-up. 
Anti-neoplastic therapies since discontinuation of study drug will be collected during the Survival 
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For the Phase 2 expansion cohorts, survival calls will be made in the 2 weeks following the date of the 
data cut-off for any OS reporting. Thus, patients may be contacted more frequently than every 12 
weeks at this time. If patients are confirmed to be alive, or if the death date is post the data cut-off 
date, these patients will be censored at the date of the data cut off in the OS reporting. Death dates 
may be found by checking publicly available death registries in line with local laws and regulations.  
 Lost to Follow Up 
For patients whose status is unclear because they fail to appear for study visits without stating an 
intention to withdraw consent, the investigator should show "due diligence" by contacting the patient, 
family, or family physician as agreed in the informed consent and by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc, a 
patient should not be considered lost to follow up until due diligence has been completed. Patients 
lost to follow up should be recorded as such on the appropriate Patient Disposition eCRF. 
 
Details of All Assessment Types 
 Efficacy Assessments 
Radiologic assessments should be performed as scheduled every 8 or 12 weeks as indicated in this 
section (See Table 7-2 below), using a reference to C1D1 and should NOT follow delays incurred in the 
treatment period. 
Tumor response will be determined according to 2 sets of criteria: 
1. RECIST v.1.1 (Appendix 1) 
2. Modified irRECIST for patients who continue treatment beyond RECISTv.1.1 disease 
progression (Appendix 2) 
For the Phase 1 cohort, the local investigator’s assessment will be used for the analysis of response 
according to RECIST v.1.1 and modified irRECIST for efficacy endpoints of the study, and for treatment 
decision making (study discontinuation due to PD as per RECISTv.1.1/modified irRECIST).  
Independent Central Review:  An ICR will be used for the analysis of ORR and all other tumor related 
endpoints based on RECIST v.1.1 and modified irRECIST for the Phase 2 cohorts. ICR of the Phase 1 
cohort may be done on an exploratory basis for patients who have consented to central reading. 
PFS will be assessed using RECIST v.1.1. Patients experiencing PD per RECIST v.1.1 criteria may consent 
to continue to be treated according to irRECIST guidelines until confirmed, unequivocal progression 
(irPD) is documented via modified irRECIST. Progression based on modified irRECIST will be assessed 
as an exploratory endpoint. 
Investigator assessment data will be used for treatment decision making during the study. 
Assessments schedule:  At Screening, all patients will undergo CT or MRI with IV contrast of the chest, 
abdomen, and pelvis.  CT imaging is preferred and MRI should only be used to evaluate sites of disease 
that are not adequately imaged by CT. If a patient is intolerant of iodine-based contrast agents, CT 
may be performed without contrast. Visible skin lesions and easily palpable subcutaneous tumors may 
be measured by physical examination using a ruler or calipers. Ultrasound should not be used to 


 
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measure sites of disease. For a given target lesion, the same imaging modality should be used 
throughout the study (CT or MRI). See Table 7-2 for further details. 
Tumor assessments will be performed at the following time points: 
 
Screening 
 
Every 8 weeks ± 1 week from C1D1 to 40 weeks (C11D1), then every 12 weeks (3 cycles) until 
PD per RECIST v.1.1 or discontinuation of study treatment. Note:  For patients who continue 
treatment beyond progression per RECISTv.1.1, imaging should continue until disease 
progression per modified irRECIST.   
 
Partial response, minor response (MinR), or complete response (CR), per both RECIST v.1.1 
and modified irRECIST, should be confirmed by a new assessment after at least 4 weeks. For 
patients who continue treatment beyond progression by RECISTv1.1, PD per modified irRECIST 
(irPD) should be confirmed after at least 4 weeks from PD by RECISTv.1.1. Further 
confirmation of irPD after its initial occurrence is not required but may be done at Investigator 
discretion.  
 
At EOT, if a scan was not conducted within 30 days prior to EOT. Note, if a patient discontinues 
treatment, but remains in Disease Progression Follow Up, then imaging visits should continue 
as per the original study plan and schedule and will not be needed at the EOT visit.  
Disease progression follow-up should be performed as described in Section 7.2.4. 
Procedure 
Screening/Baseline 
During Treatment/Follow Up 
CT or MRI 
with contrast 
enhancement 
(chest, abdomen, 
pelvis) 
Mandatory 
Mandatory, every 8 weeks from C1D1 until 
C11D1 (40 weeks), then every 12 weeks until 
progressive disease per RECISTv1.1, irPD per 
modified irRECIST for patients who continue 
treatment beyond PD per RECISTv1.1  or 
discontinuation of study treatment 
The same imaging modality should be used 
throughout the study (CT or MRI) 
At EOT, if a scan was not conducted within 30 
days prior to EOT. Note, if a patient discontinues 
treatment, but remains in Disease Progression 
Follow Up, then imaging visits should continue 
as per the original study plan/schedule and will 
not be needed at the EOT visit 
Brain MRI with 
contrast 
Required only if clinical 
suspicion of brain 
metastasis at Screening 
If disease was detected at Baseline, or if 
clinically indicated 
C#D# = Cycle # Day #; CT = computed tomography scan; EOT = end of treatment; MRI = magnetic 
resonance imaging; RECISTv1.1 = Response Evaluation Criteria in Solid Tumors version 1.1. 
Table 7-2 
Disease Assessment Collection Plan 


 
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7.3.1.1 Independent Central Review 
All on-study images acquired for tumor and treatment effect assessments will be submitted to an 
imaging contract research organization (CRO) for further blinded, independent, central review for 
analysis. A central imaging manual will be provided to all investigative sites detailing the procedures 
for de-identification and submission of imaging studies for central review. For endpoints assessed by 
ICR, review of all radiological imaging data will be carried out. All radiological scans for all patients 
(including those at unscheduled visits, or outside visit windows), will be provided to the ICR. Further 
details of the ICR procedures and processes will be included in the study imaging manuals.  
All patient management decisions will be based upon local assessment of imaging studies at the site 
and not on the ICR. 
 Safety and Tolerability Assessments 
Safety will be monitored by assessing physical examination, vital signs, body height and weight, 
performance status, hematology, chemistry, coagulation, urinalysis, thyroid function, pregnancy, ECG, 
cytokine testing. AE are collected at every visit. For details on AE collection and reporting, refer to 
Section 8.  
 Physical Examination 
Physical examination will be performed according to Table 7-1. 
At Screening and C1D1, prior to IMCgp100 infusion, a complete physical examination will be 
performed and will include the examination of general appearance, skin, neck (including thyroid), 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and neurological 
system. If indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and 
pelvic exams will be performed. 
From C1D8 onwards, a short physical examination will be performed prior to IMCgp100 infusion. A 
short physical exam will include the examination of general appearance, vital signs (temperature, 
blood pressure, respiratory rate and pulse) and body sites as directed by symptoms. 
Significant findings that were present prior to the signature of the informed consent must be included 
in the Medical History eCRF page. Significant new findings that begin or worsen after informed consent 
must be recorded on the AE eCRF page. 
 Vital Signs 
Vital signs (body temperature, pulse rate, respiratory rate, and blood pressure) must be performed 
before dosing and after the IMCgp100 administration as indicated in Table 7-1 and Table 7-3, and as 
per institutional standards. 
Vital signs should be assessed on the scheduled day, even if study treatment is being withheld. More 
frequent examinations may be performed at the discretion of the investigator if medically indicated, 
and will be recorded as unscheduled assessments.  
See Section 6.2 for additional details on intra-patient dose escalation regimen. 
 


 
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C1D1, 
C1D8, 
C1D15 
Inpatient 
monitoring 
required for all patients 
Vital signs monitored per institutional standards at a minimum of 
every 4 hours. Patients should be monitored for at least 16 hours 
after dosing. 
 
Patients experiencing Grade 2 or greater hypotension at 
C1D15 require inpatient monitoring for the subsequent/next 
C1D22 dose. 
 
Those experiencing Grade 3 or 4 hypotension at C1D1, C1D8 
or C1D15 require hourly VS monitoring for minimum of 8 
hours after dosing for any doses administered as outpatient 
through C2D15.  
C1D22 
Inpatient 
monitoring required for 
exception noted  
Patients experiencing a grade 2 or greater hypotension at C1D15 
must be observed as an inpatient for C1D22 dose, with VS performed 
at a minimum of every 4 hours and monitoring for at least 16 hours 
after dosing.  
C1D22 
through 
C2D15 
Monitoring 
requirements 
for exceptions noted 
Patients experiencing Grade 3 or 4 hypotension at C1D1, C1D8 or 
C1D15 require hourly VS monitoring for minimum of 8 hours after 
dosing for any doses administered as outpatient through C2D15.  
 
If patient experienced ≥ Grade 2 hypotension at C1D15, they 
must be monitored as inpatient for C1D22, as noted above. 
C2 and later cycles- Days 1, 
8, 15 and 22  
Outpatient monitoring 
For patients without Grade 2 or greater hypotension at C1D15 or 
Grade 3 or 4 hypotension at C1D1, C1D8 or C1D15, outpatient VS 
must be monitored in clinic for minimum of one hour after infusion 
with at least 2 post-dose VS measurements performed.  
For patients who have received outpatient treatment with 
IMCgp100 for at least 3 months, outpatient monitoring in clinic may 
be decreased to minimum of 30 minutes post dosing after 
discussion with Sponsor Medical Monitor. 
Treatment breaks/delays 
Patients with break or delay in treatment for >2 weeks AND with 
history of a grade 3 or 4 hypotension with IMCgp100 dosing during 
the first weeks of treatment will be monitored as an inpatient for the 
dose subsequent to/following the break in dosing, with VS performed 
at a minimum of every 4 hours and monitoring for at least 16 hours 
after dosing. 
 
 Height and Weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but 
without shoes) will be measured as indicated in Table 7-1. 
Table 7-3 
Post Dose Vital Signs Monitoring 


 
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 Eastern Cooperative Oncology Group Performance Status 
Performance status is determined as indicated in Table 7-4 and should be determined on Day 1 of all 
odd-numbered cycles (e.g., C1D1, C3D1, C5D1, etc) and at EOT. 
Grade 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5 
Death 
ECOG = Eastern Cooperative Oncology Group. 
 Laboratory Evaluations 
All laboratory parameters assessed for safety purposes will be evaluated locally. Refer to Table 7-5 for 
a summary of the parameters to be evaluated according to Table 7-1. On dosing days of IMCgp100, 
samples for these parameters will be collected prior to the infusion of IMCgp100, and may be collected 
1 day prior to dosing. 
More frequent evaluations may be performed at the investigator’s discretion if medically indicated; 
results should be recorded as unscheduled laboratory assessments. 
Immunocore or the designated CRO will be provided with a copy of the laboratory certification and 
tabulation of the normal ranges for each parameter required. In addition, if at any time a patient has 
laboratory parameters obtained from a different outside laboratory, Immunocore or the CRO must be 
provided with a copy of the certification and a tabulation of the normal ranges for that laborator
Table 7-4 
Eastern Cooperative Oncology Group Performance Status 


 
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Test Category 
Test Name 
Hematology 
Hematocrit, hemoglobin, platelets, white blood cells with differential 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils) 
Chemistry 
Albumin, alkaline phosphatase, alanine transaminase, aspartate 
transaminase, bicarbonate, calcium, chloride, creatinine, glucose 
magnesium, phosphate, potassium, sodium, total bilirubin (also measure 
direct and indirect bilirubin if total bilirubin is > grade 1), blood urea nitrogen 
or urea, amylase, lipase, lactate dehydrogenase.  
Inflammatory 
Analytes 
C-reactive protein (CRP) and lactate dehydrogenase (LDH). 
Coagulation 
Prothrombin time or international normalized ratio, activated partial 
thromboplastin time 
Urinalysis 
Macroscopic panel (dipstick) (bilirubin, blood glucose, ketones, pH, protein, 
specific gravity, white blood cells) 
Thyroid 
Free T4, thyroid stimulating hormone 
 
 
 
7.3.7.1 Hematology 
Hematology panel outlined in Table 7-5 will be performed as per the assessment schedule in  
Table 7-1. 
7.3.7.2 Clinical Chemistry 
Clinical chemistry panel outlined in Table 7-5 will be performed as per the assessment schedule in 
Table 7-1.  Note: Serum calcium is measured and recorded in the eCRF.  For purposes of eligibility 
assessment and AE grading, calcium should be corrected for abnormal albumin measurements. 
7.3.7.3 
 
 
 
. 
7.3.7.4 Coagulation 
Coagulation panel outlined in Table 7-5 will be performed as per the assessment schedule in 
Table 7-1. 
7.3.7.5 Urinalysis 
Urinalysis panel outlined in Table 7-5 will be performed as per the assessment schedule in Table 7-1. 
7.3.7.6 Thyroid Function 
Thyroid function panel outlined in Table 7-5 will be performed as per the assessment schedule in 
Table 7-1. 
Table 7-5 
Local Clinical Laboratory Parameters Collection Plan 


 
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7.3.7.7 
 
 
 
 
 
 
Within 5 hours after the occurrence of the AE 
 
1 week after the occurrence of the AE 
7.3.7.8 Pregnancy and Assessment of Fertility 
Pregnancy tests will be performed for women of child bearing potential. 
At Screening, a serum pregnancy test must be performed within 72 hours before the first dose. During 
the study (Day 1 of each cycle starting with Cycle 2 and prior to study drug dosing) a serum or urine 
pregnancy test must be performed. At EOT, a serum or urine pregnancy test must also be performed. 
7.3.7.9 Cardiac Assessments 
A standard 12-lead ECG will be performed as per the assessment schedule in Table 7-1 and 
Table 7-6. Blood samples scheduled at the same time point should be taken after the ECGs are 
completed.  
Clinically significant abnormalities present at Screening should be reported on the Medical History 
eCRF page. New or worsened clinically significant findings occurring after informed consent must be 
recorded on the AE eCRF page.  
Cycle 
Day 
Time
Screening 
-21 to -1 
Anytime 
1 
1 
Pre-dose 
1 
1 
1 hour post dose** 
2 
1 
Pre-dose 
2 
1 
1 hour post dose  
3 
1 
Pre-dose 
3 
1 
1 hour post dose  
5 
1 
Pre-dose 
5 
1 
1 hour post dose  
EOT 
- 
Anytime 
Unscheduled* 
- 
As clinically indicated based on symptoms and/or exam 
EOT = end of treatment; RP2D-IE = recommended Phase 2 dose — intra-patient escalation. 
‡ During the RP2D-IE expansion cohorts, electrocardiogram assessments will be performed during Screening, 
Cycle 1 pre- and post-dose, Cycle 2 pre- and post-dose, Cycle 3 pre- and post-dose, Cycle 5 pre- and post-
dose, and at EOT. 
* An unscheduled pharmacokinetic sample should be collected just after an electrocardiogram is performed due 
to any unexpected cardiac signal. 
**ECG should be collected between the end of infusion and 1 hour post dose. 
NOTE:  When ECGs are scheduled at the same time as blood draws, the ECG should be done prior to the blood 
draw. 
Table 7-6 
12-lead Electrocardiogram Collection Plan‡ 


 
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7.3.7.10 
Skin Punch Biopsy 
An OPTIONAL skin punch biopsy is to be taken in patients experiencing a ≥ grade 3 rash, bullous rash 
of any grade, or worsened rash on C1D15 or beyond. Rash that worsens is defined as increase in grade 
or increased symptoms associated with the rash (e.g., pruritus) compared to skin toxicity observed on 
IMCgp100 dosing days, C1D1 or C1D8. Skin biopsies will be assessed for immune infiltrate 
characteristics, gp100 expression, and other markers of immune activation (e.g., HLA-DR, PD-L1) to 
determine the immune activation status in the skin and potentially the mechanisms of skin toxicity.  
 Pharmacokinetics and Immunogenicity Assessments 
The PK and Immunogenicity blood samples should be taken according to Table 7-7. Details are also 
described in the laboratory manual for the handling, labelling and shipment of the PK and 
Immunogenicity blood samples. It is essential that the actual time and date of collection of each blood 
sample be recorded on the patient’s eCRF.  
All PK samples have a collection window of ± 1 hour, with the exception of the post-infusion time point 
which should be collected after the infusion completes and within 15 minutes of the completion time 
of the IMCgp100. PK samples on C1D2 and Cycle 1 Day 16 (C1D16) at the last post-infusion time point 
should be collected anytime in the 12- to 24-hour window after the completion of the IMCgp100 
infusion. The time that the sample was collected must be reported with the sample.  
Blood samples for the determination of IMCgp100 concentration time profiles in serum will be 
obtained throughout the study. The volume of blood to be collected per sample should be 2 mL to 
provide approximately 1 mL of serum split into 2 aliquots of 0.5 mL each. 
Blood samples to look for the formation of any IMCgp100 anti-drug antibodies will be obtained 
throughout the study.


 
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Table 7-7 
Pharmacokinetic Assessments 
Day of 
Treatment 
Pharmacokinetic 
Sample Timing  
Dose Escalation 
Pharmacokinetic 
Sample Timing  
RP2D-IE 
Immunoglobulin 
Sample Timing 
C1D1 
Pre-dose 
Pre-dose 
Pre-dose^ 
C1D1 
End of infusion 
End of infusion 
 
C1D1 
4-hour post-dose 
4-hour post-dose 
 
C1D1 
8-hour post-dose^^ 
 
 
C1D2 
12- to 24-hour post-
dose^^ 
12- to 24-hour post-
dose^^ 
 
C1D8 
Pre-dose 
Pre-dose 
Pre-dose^ 
C1D8 
End of infusion 
End of infusion 
 
C1D15 
Pre-dose 
Pre-dose 
 
C1D15 
End of infusion 
End of infusion 
 
C1D15 
4-hour post-dose 
4-hour post-dose 
 
C1D15 
8-hour post-dose^^ 
 
 
C1D16 
12- to 24-hour post-
dose^^ 
12- to 24-hour post-
dose^^ 
 
C1D22 
Pre-dose 
 
 
C1D22 
End of infusion 
 
 
C2D1 
Pre-dose 
Pre-dose 
Pre-dose^ 
C2D1 
End of infusion 
End of infusion 
 
C2D15 
Pre-dose 
 
 
C2D15 
End of infusion 
 
 
C3D1 
Pre-dose 
Pre-dose 
Pre-dose^ 
C3D1 
End of infusion 
End of infusion 
 
C3D15 
Pre-dose 
 
 
C3D15 
End of infusion 
 
 
CXD1* 
Pre-dose 
Pre-dose 
Pre-dose^ 
CXD1* 
End of infusion 
End of infusion 
 
EOT 
 
At visit^ 
At visit^ 
C#D# = Cycle#Day#; EOT = end of treatment; RP2D-IE = recommended Phase 2 dose — intra-
patient escalation.  
All PK samples have a window of ± 1 hour, with exception of the end of infusion time point which 
should be collected 15 minutes after the completion of the IMCgp100 infusion. 
* “CX” will refer to Cycle 6 and then every 3rd cycle (e.g., C9, C12, etc.).  
^ Immunoglobulin samples will be taken pre-dose at C1D1, C1D8, C2D1, C3D1 and then every 3rd 
cycle starting at C6 (“CX”), at the End of Treatment Visit. 
^^ Pharmacokinetic sample should be obtained in the timeframe just prior to discharge. The time of 
sample must be recorded in the eCRF.  


 
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7.4.3.4 
  
 
 
 
 
 
   


 
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8 ADVERSE EVENTS AND SAFETY REPORTING 
 
Assessment of Safety 
All patients who receive any treatment with IMCgp100 will be considered evaluable for safety. All AE 
regardless of study drug relationship will be collected up to the 90-day follow-up. 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies are 
crucial for the protection of patients and is mandated by regulatory agencies worldwide. The Sponsor 
and CRO have established standard operating procedures in conformity with regulatory requirements 
worldwide to ensure appropriate reporting of all safety information; all clinical studies conducted by 
the Sponsor or its affiliates will be conducted in accordance with those procedures. 
Individual AEs should be evaluated by the investigator and should be reported to the CRO/Sponsor for 
evaluation. This includes the evaluation of the event’s seriousness and the causality between the 
investigational medicinal product(s) and/or concomitant therapy and the AE. The CRO/Sponsor is 
required to maintain detailed records of all AEs reported by the investigator(s) and to perform an 
evaluation with respect to seriousness, causality, and expectedness. On request of a competent 
authority in whose territory the clinical trial is being conducted, the sponsor should submit detailed 
records of all AEs which are reported to him by the relevant investigators. Case report processing 
concerns evaluation of data in individual cases, identification of individual cases requiring specific 
handling, recognition and processing of alerts, and any other data processing of aggregated cases. 
 Definitions 
Definitions of AEs, adverse drug reactions, SAEs and unexpected adverse drug reactions and AEs of 
special interest are presented below. 
AE:  An AE is defined as the appearance of (or worsening of pre-existing) an undesirable sign, 
symptom, or medical condition that occurs after patient’s signed informed consent has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute AEs only if they 
induce clinical signs or symptoms, are considered clinically significant, require therapy (e.g., 
hematologic abnormality that requires transfusion or hematological stem cell support), or require 
changes in study medication. 
Adverse drug reaction:  is an unwanted or harmful reaction which occurs after administration of a 
drug or drugs and is suspected or known to be due to the drug. Adverse drug reactions have 
traditionally been categorized as pharmacologic (predicted based on the pharmacology of the drug) 
or idiosyncratic (not predicted based on pharmacology). 
SAE:  A SAE is any AE that is defined as 1 of the following: 
1. Is fatal or life-threatening  
2. Results in persistent or significant disability or incapacity 
3. Constitutes a congenital anomaly/birth defect 
4. Is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent 1 of the outcomes listed above 


 
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5. Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 
Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 
Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
6. Death due to the progression of malignancy should not be reported as a SAE, if documented 
by use of appropriate method (e.g., as per RECIST v.1.1). Any AE that occurred as a result of 
the PD should be reported in the appropriate manner 
Unexpected adverse drug reaction:  An adverse drug reaction that is not consistent with applicable 
product information or characteristics of the study drug. 
Suspected, unexpected, serious adverse reaction (SUSAR):  A SUSAR is an adverse reaction meeting 
serious criteria (above), the nature or severity of which is not consistent with the reference safety 
information for the investigational drug(s). 
Adverse events of special interest (AESI):  An AESI (serious or non-serious) is an AE with scientific 
and/or medical concern specific to the Sponsor’s program, for which ongoing monitoring and rapid 
communication by the investigator to the Sponsor can be appropriate. Refer to the IMCgp100 
Investigator’s Brochures for details of the AESI. 
 
Criteria for Expectedness 
The concept of expectedness refers to events that may or may not have previously been observed and 
documented and not necessarily the known pharmacological properties of the medicine. An AE will 
be unexpected for purposes of regulatory reporting unless it is mentioned in the appropriate 
reference safety information within the current Investigator’s Brochure for the investigational drug, 
even if it is a medical occurrence expected for the disease being treated. 
 
Assessment of Causality 
 Causality Assessment Required for all Adverse Events 
The investigator decides whether he or she interprets the observed AE as either related to disease, to 
the study medication, study procedure, or other concomitant treatment or pathologies. To assess the 
relationship of the AE to the study drug, the following terms are defined:    
1. Related:  a direct cause and effect relationship between the study treatment and the AE is 
likely   
2. Possibly related:  a cause and effect relationship between the study treatment and the AE has 
not been demonstrated at this time and is not probable, but is also not impossible   


 
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3. Unrelated:  without question, the AE is definitely not associated with the study treatment 
All “related” and “possibly related” AEs and SAEs will be defined as related to study drug. 
 
Adverse Event Reporting 
 Expedited Reporting 
Cases of adverse drug reactions from all sources that are assessed as serious are subject to expedited 
reporting. Expedited reporting of cases will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/ IEC and Investigators. Additionally, any 
safety information from other observations that could change the risk benefit evaluation of the 
product will be communicated in an expedited manner to the regulatory authorities and all 
investigators by the Sponsor.  
The CRO will be responsible for the processing and reporting of SAEs. AEs will be coded by using ICH 
Medical Dictionary for Regulatory Activities. 
Minimum criteria for a valid adverse drug reaction case have been established by ICH and individual 
regulatory agencies and are listed as the following: 
 
An identifiable reporter 
 
An identifiable patient 
 
A reaction/event 
 
A suspected medicinal product 
Other safety issues that also qualify for expedited reporting by the Sponsor are those that would 
materially alter the current benefit risk assessment of the investigational product (sufficient to 
consider changes in the administration or in the overall conduct of the trial). Although these events 
will not be reported as SUSARs, they might require other action, such as putting in place urgent safety 
measures, the generation of substantial amendments, or early termination of the trial. The Sponsor 
will inform the regulatory authorities and all IEC of safety issues which might materially alter the 
benefit-risk assessment of the investigational agents. 
 Standards for Expedited Reporting 
Cases of adverse drug reactions from all sources that are assessed as SUSARs are subject to expedited 
reporting. Additionally, any safety information from other observations that could change the risk 
benefit evaluation of the product should be promptly communicated to the regulatory authorities. 
Any other SUSARs associated with the investigational product should be reported as soon as the 
Sponsor becomes aware of them and this includes SUSARs which occur in another trial conducted by 
the same Sponsor, or which are identified by spontaneous reports or a publication, or which are 
transmitted to the Sponsor by another regulatory authority. 


 
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 Reporting of Out-of-range Laboratory Test Results as Adverse Events 
Out-of-range laboratory test results should be reported as AEs (not as abnormal laboratory values, 
i.e., report as anemia not low hemoglobin) if, in the opinion of the principal investigator, they are 
clinically significant. Abnormal laboratory results that are not considered to be clinically significant will 
not be reported as AEs. Significance of abnormal laboratory results should be documented in the study 
records.  
 Reporting Guidelines for Other Observations 
Other safety issues that also qualify for expedited reporting where they might materially alter the 
current benefit risk assessment of the investigational product (sufficient to consider changes in the 
administration or in the overall conduct of the trial), for instance include: 
 
An increase in the rate of occurrence of an expected serious adverse reaction, which is judged 
to be clinically important 
 
A post study SUSAR that occurs after the patient has completed a clinical trial and is reported 
by the investigator to the Sponsor 
Events which occur during the trial and are relevant in terms of patient safety, but which do not fall 
within the definition of SUSAR (and thus are not subject to the reporting requirements for SUSARs) 
are:   
 
An SAE which could be associated with the trial procedures and which could modify the 
conduct of the trial 
 
A significant hazard to the patient population such as lack of efficacy of an investigational 
medicinal product 
 
A major safety finding from a newly completed animal study (such as carcinogenicity) 
 
A temporary halt of a trial for safety reasons if the trial is conducted with the same 
investigational medicinal product in another country by the same Sponsor 
 
Safety recommendations of the Independent Data Monitoring Committee (IDMC) 
Although these events/observations will not be reported as SUSARs, they might require other action, 
such as putting in place urgent safety measures, the generation of substantial amendments, or early 
termination of the trial. The Sponsor will inform the regulatory authorities and the IECs of safety issues 
which might materially alter the benefit-risk assessment of the investigational medicinal product. 
Expedited reporting is not usually required for reactions that are serious but expected, or for non-
serious adverse reactions whether expected or not. 
It is usually also inappropriate to report events that are considered unrelated to the investigational 
medicinal product. 


 
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 Pregnancy Reporting 
Pregnancy will be reported through the Pregnancy Reporting Form (paper) as well as in the eCRF as 
an AE. The Pregnancy form (paper) should be completed and reported as indicated to the CRO 
Pharmacovigilance Team within 24 hours of being made aware of the event. Pregnancy will be 
considered as an AE and also reported in the eCRF. Women who become pregnant during the study 
will be withdrawn from treatment at the earliest opportunity. The investigator shall report all 
pregnancies immediately to the CRO. The CRO will then notify the Sponsor within 1 business day of 
being informed of the event. Following withdrawal from the study, every attempt will be made to 
follow the patient and any resulting offspring for up to 6-weeks postpartum, unless otherwise 
medically indicated. Abortion, stillbirth, or any malformation/disease in the offspring must be 
reported as an SAE.  
For men participating in the study who report the pregnancy of a partner, the investigator will ask to 
collect information about the results of the pregnancy/birth using the Pregnant Partner forms. The 
partner may be asked to sign a consent form giving permission for information to be collected. This 
health information will become part of the research study records. It will be shared with the Sponsor. 
 
Investigator’s Responsibilities 
The investigator is responsible for the collection of AE data. All AEs should be recorded in the eCRF. 
The investigator shall report all SAEs immediately within 24 hours of being made aware of the event 
to Pharmacovigilance via the clinical database by completing as much information as possible and 
checking Yes when prompted whether the event is classified as an SAE in the AEs eCRF. The initial 
reporting can be supplemented by written reports using the SAE report form provided.  
The follow up reports (if required) shall identify the trial patients by unique code numbers assigned to 
the patient. The investigator shall supply the Sponsor with any additional requested information, 
notably for reported deaths of a patient. 
All SAEs that occur between obtaining the patient’s Informed Consent and 90 days after the last dose 
of study drug must be reported promptly to the CRO not later than 24 hours after the investigators or 
co-investigators become aware of their occurrence using the SAE eCRF in the study database. 
The SAE eCRF is accessed via the study database. The following minimum information is required for 
the report: 
 
Patient identification (patient number and date of birth) 
 
Trial number 
 
Study therapy (dose, route, form, regime, start date, end date) 
 
Concomitant medication (including dose, route, form, regime, start date where available) 
 
Nature of SAE (overall diagnosis where available or alternatively signs and symptoms) 
 
Date and time of occurrence 
 
Any associated factors (concomitant disease or medication) 
 
Proposed relationship to study therapy 


 
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 
Outcome 
 
Identify the reporter 
 
Action in relation to study (withdrawn from treatment, suspended, none) 
The investigators or co-investigators are required to sign the SAE submission electronically in the 
clinical database within 24 hours of awareness of the event, even if the required information is 
incomplete or if the investigators are awaiting laboratory or diagnostic reports. Investigators may be 
asked for additional information for any reported SAE. An SAE follow up report with attached 
documents (if necessary) should be forwarded to CRO Pharmacovigilance as soon as the additional 
information is available by email. The study number IMCgp100-102 must be in the title of any email 
for study identification purposes.  
 
Sponsor and Clinical Research Organization’s Responsibilities 
The Sponsor is responsible for the ongoing safety evaluation of the investigational drugs being studied. 
The Sponsor and CRO are responsible for ensuring that expedited reports are made to all concerned 
investigators, to the IEC where required, and to all regulatory authorities of all adverse drug reactions 
that are both serious and unexpected, or findings that could adversely affect the health of patients, 
impact on the conduct of the trial, or alter the competent authority’s authorization to continue the 
trial in accordance with local applicable regulations. 


 
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9 STATISTICAL METHODS AND DATA ANALYSES 
 
General Principles 
Data from Phase 1 will be summarized after approximately 80% of patients in Phase 1 have completed 
study treatment. Data will be presented by dose cohort and overall. At the end of Phase 2, any 
additional data collected for patients remaining on treatment after the Phase 1 data cut-off will be 
included in the final clinical study report. 
For the Phase 1 escalation cohort, data will be reported based on all patient data up to the time when 
all patients have completed a minimum of 6 cycles of treatment or have discontinued the study. An 
updated analysis of DOR, PFS, and OS may be performed. Data will be presented by dose cohort and 
overall. 
For the Phase 2 expansion cohort, the primary analysis of the study will be conducted after 
approximately 120 evaluable patients have been enrolled and treated/followed for at least 9 months. 
The primary analysis of Phase 2 will summarize data from the overall expansion cohort (approximately 
n=120 patients).  
In order to explore whether results are consistent across prior therapy groups, key endpoints may be 
further summarized by prior therapy groups (for example:  1 systemic therapy and 1 LDT; 1-2 systemic 
therapies only; 1 LDT only, 1 checkpoint inhibitor and any LDT). Further details around the analysis 
plan, including any additional reporting of DOR, PFS, and OS with longer-term follow up that may be 
required will be defined in the Statistical Analysis Plan (SAP). 
Data will be summarized using descriptive statistics. Categorical data will be presented as frequencies 
and percentages. For continuous data, mean, standard deviation, median, minimum, and maximum 
will be presented. 
The following rules will be followed for reporting results unless stated otherwise: 
 
Screen failure patients are those who signed the informed consent, but never started the 
study treatment for any reason. For these patients, the eCRF data collected will not be 
included in analyses, but will be reported in the clinical study report as separate listings 
 
Baseline is defined as the last assessment prior to the first dose of treatment received (i.e., 
C1D1 pre-dose) 
 
Additional analyses not described here will be detailed in the SAP for the study 
 
Analysis Sets 
 Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients assigned to treatment, who received at least 1 full or 
partial dose of IMCgp100. The FAS will be used for all demography, baseline characteristics, and 
efficacy data summaries and analyses.  


 
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 Safety Analysis Set 
The Safety Set includes all patients who have received at least 1 full or partial dose of IMCgp100. 
Patients will be classified in this set according to initial treatment received. The safety set will be used 
for the safety summary of the study. 
 Per-protocol Analysis Set 
The Per Protocol Set (PPS) consists of a subset of FAS patients who meet these 4 criteria:  (1) presence 
of measurable disease, (2) 1 post-baseline tumor assessment or discontinue prior to the first tumor 
assessment,  (3) received at least 1 dose of treatment and, (4) no violation of key inclusion or exclusion 
criteria.  
Patients in the PPS will be classified according to planned treatment. The PPS will define the patients 
used in the sensitivity analysis of the secondary endpoints. If the PPS and the FAS are identical, then 
analyses described by the PPS below will not be performed. 
 
Patient Demographics and Other Baseline Characteristics 
Demographic data, baseline disease characteristics and other baseline data will be listed in detail. 
Qualitative data (e.g., performance status) and quantitative data (e.g., weight) will be summarized by 
descriptive statistics. 
 
Treatment Data 
Actual dose and duration in days of treatment for IMCgp100, as well as, the dose intensity (actual dose 
received/actual duration) and relative dose intensity (the ratio of dose intensity to planned 
dose/planned duration) will be summarized by descriptive statistics by treatment group.  
Concomitant medications and significant non-drug therapies prior to and after the start of the study 
treatment will be listed by patient and summarized by Anatomical Therapeutic Chemical term and 
treatment group. 
The reason for discontinuation from treatment will be summarized and listed, along with dates of first 
and last doses, duration of exposure to each study drug, and date of discontinuation for each patient. 
 
Primary Analysis 
 Variables 
The primary variable in the Phase 1 dose escalation phase of the study is the incidence of DLT. 
The primary variable in the Phase 2 dose expansion phase of the study is ORR by RECISTv.1.1 assessed 
by ICR. 


 
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Secondary Analyses 
 Efficacy 
Analysis of efficacy endpoints will be performed using the FAS unless otherwise noted. 
For the Phase 1 escalation cohorts, tumor-based endpoints will be assessed using local investigator 
assessment and ICR where available for both RECISTv.1.1 and modified irRECIST. For the Phase 2 
expansion cohorts, tumor-based endpoints will be assessed using ICR data for both RECIST v1.1 and 
modified irRECIST. ORR and other RECIST-based endpoints as assessed by the local radiologist will be 
summarized as a sensitivity analysis. 
ORR is defined as the proportion of patients with measurable disease with at least 1 visit response of 
CR or PR that is confirmed at least 4 weeks later, as defined in RECIST v.1.1.  
The denominator in the calculation of the ORR will be the number of patients in the FAS with 
measurable disease at baseline. Data obtained up until progression, or last evaluable assessment in 
the absence of progression, will be included in the assessment of ORR. However, any CR or PR, which 
occurred after further anti-cancer therapy was received, will not be included in the numerator of the 
ORR calculation. Disease control rate is defined as the proportion of patients with a best overall 
response of CR or PR or SD recorded at least 24 weeks (± 1 week) after commencement of study drug 
and prior to any PD event. 
For all efficacy parameters, data will be listed, summarized, or analyzed by treatment group (dose 
cohort) for the Phase 1 dose escalation and overall for the Phase 2 expansion cohorts.  
In order to explore whether the Phase 2 efficacy results are consistent across prior therapy groups, 
key endpoints (including ORR and DoR) may be further summarized by prior therapy groups (for 
example:  1 systemic therapy and 1 LDT; 1-2 systemic therapies only; 1 LDT only, 1 checkpoint inhibitor 
and any LDT).  
Further subset analyses of efficacy by LDH (above or below institutional ULN) and hepatic metastases 
(present or absent) may be performed if an adequate number of patients with and without the 
prognostic factor are available for analysis (Valpione, 2015). 
ORR and DCR will be summarized with accompanying 95% confidence intervals. 
PFS, along with DOR and time to response for patients who experience a CR or PR at any time on study 
will be listed by patient. 
PFS will be presented graphically using Kaplan Meier plots for all patients in the Phase 2 expansion 
cohorts. Median PFS time and the proportion of patients who are progression-free at 3, 6, 9, and 12 
months will also be estimated. If there are a large number of patients achieving response (e.g., 
estimated ORR of 30%), the Kaplan-Meier plots for DOR will also be produced and the median DOR 
will be estimated. OS will be presented graphically using Kaplan Meier plots including all patients from 
the Phase 2 expansion. Median OS time and the proportion of patients who are alive at 3, 6, 9, and 12 
months will be estimated. 
The secondary endpoint to determine the rate and duration of MinR, defined as a reduction in the SLD 
of 10%–29% will be explored by:  (1) summaries of the number (%) of MinR and associated durations; 
(2) summaries of the overall ORR + MinR and associated durations; and (3) waterfall plots of SLDs. 


 
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The secondary endpoint to determine the rate and duration of immune responses will be detailed in 
the SAP and be largely based on methods described by Gao et al. In summary, for each patient, the 
percentage change in the target lesion sum of longest diameters will be plotted over time and an AUC 
will be calculated over a fixed time-period (e.g., 9 months) post initial dose of IMCgp100. The AUC 
reflects both the depth and duration of tumor size reduction and may capture a delayed benefit of 
immunotherapy (Gao et al). Hepatic volume data will also be plotted and may be incorporated into 
the criteria for immune response. 
Exploratory tumor assessments based on modified irRECIST will also be presented summarizing the 
best response by irRECIST and this will be compared with the best response from RECISTv.1.1. 
The SAP will provide more detailed information on the data summaries for the Phase 1 dose escalation 
and the Phase 2 dose expansion.  
 
 
 
 
 
 
 
  
 Safety Objectives 
9.6.2.1 Analysis Set and Grouping for the Analyses 
For all safety analyses, the safety set will be used.  
The overall observation period will be divided into 3 mutually exclusive segments: 
1. Pre-treatment period:  from day of patient’s informed consent to the day before first dose of 
study medication 
2. On-treatment period:  from day of first dose of study medication to 90 days after last dose of 
study medication 
3. Post-treatment period:  starting at Day 31 after last dose of study medication 
9.6.2.2 Adverse Events 
Summary tables for AEs include only AEs that are new or worsened during the on-treatment period 
(treatment-emergent AEs). However, all safety data (including those from the pre- and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period are to 
be flagged. 


 
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The incidence of treatment-emergent AEs will be summarized by system organ class and/or preferred 
term, severity (based on NCI CTCAE v.4.03 grades), type of AE, and relation to study treatment by 
treatment group. Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated 
by type of AE and treatment group. 
Definitions of notably abnormal vital signs results (e.g., hypotension) will be specified in the SAP and 
a shift table baseline to worst on-treatment result will be produced by the Phase 1 dose escalation 
and Phase 2 dose expansion groups. 
9.6.2.3 Laboratory Abnormalities 
For laboratory tests covered by the NCI CTCAE version 4.03 the study team will grade laboratory data 
accordingly. For laboratory tests covered by NCI CTCAE, a grade 0 will be assigned for all non-missing 
values not graded as 1 or higher. For laboratory tests where grades are not defined by CTCAE, results 
will be graded by the low/normal/high classifications based on laboratory normal ranges. 
The following by-treatment summaries will be generated separately for hematology, biochemistry, 
and other laboratories: 
 
Frequency table for newly occurring on-treatment grades 3 or 4 and all grades 
 
Shift tables of laboratory and ECG data using CTCAE grades to compare Baseline to the worst 
on-treatment value 
 
Listing of all clinically relevant laboratory data and relevant ECG data with values flagged to 
show the corresponding CTCAE grades and the classifications relative to the laboratory normal 
ranges 
9.6.2.4 Other Safety Variables 
 
Vital signs absolute values and changes from Baseline will be summarized. Normal ranges will be 
specified in the SAP and shift tables of Baseline to worst on-treatment results will be produced 
 
ECG data:  QTc interval absolute values and changes from Baseline will be summarized. 
Abnormalities will be classified according to NCI CTCAE grades and shift tables of Baseline to worst 
on-treatment results will be presented  
 
Physical examination data will be listed and abnormalities will be flagged 
9.6.2.5 Tolerability 
Tolerability of study treatment will be assessed by summarizing the number of treatment dose 
interruptions and dose reductions. Reasons for dose interruptions and dose reductions will be listed 
by patient and summarized. 
9.6.2.6 Pharmacokinetics 
The PK parameters that will be assessed are presented in Table 9-1. 


 
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AUClast 
The area under the curve (AUC) from time 0 to the last measurable concentration 
sampling time (tlast) (mass x time x volume-1) 
AUCinf 
The AUC from time 0 to infinity (mass x time x volume-1) 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time) 
T1/2 
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives 
CL 
The total body clearance of drug from the plasma (volume x time-1) 
Vz 
The apparent volume of distribution during terminal phase (associated with z) 
(volume) 
AR 
Accumulation Ratio=Cmax (multiple dose)/Cmax (single dose) 
The safety set will be used in all PK data analysis and PK summary statistics. 
Pharmacokinetic Analyses 
Descriptive statistics of all PK parameters for IMCgp100 will include arithmetic and geometric mean, 
median, stable disease, and coefficient of variation, geometric coefficient of variation, and minimum 
and maximum. Zero concentrations will not be included in the geometric mean calculation. Since Tmax 
is generally evaluated by a non-parametric method, median values and ranges will be given for this 
parameter. Missing concentration values will be reported as is in data listings. Concentration values 
below lower limit of quantitation will be handled as 0 in summary statistics, and reported as is in data 
listings. Any missing PK parameter data will not be imputed. 
Further analyses may be conducted using population PK approaches. In addition, a model based 
approach may be used to explore the potential relationship between efficacy, safety, and/or 
biomarker endpoints and IMCgp100 concentration and/or exposure metrics. All analyses will be 
reported either in the clinical study report or a stand-alone report. 
The concentration-/AE-immunogenicity relationship will be explored graphically and tabulated to 
characterize a relationship between the changes from screening immunogenicity presence and serum 
concentration of IMCgp100. Further details will be described in the SAP. 
 
Exploratory Analyses 
 
 
 
 
  
Table 9-1 
Pharmacokinetic Parameters to be Analyzed 


 
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9.7.1.2 
 
 
 
 
  
 
 
 
Interim Analysis 
For the Phase 1 cohorts, the dose-escalation design foresees that decisions based on the current data 
are taken before the end of the study. More precisely, after each cohort in the dose escalation part, 
the next dose will be chosen depending on the observed data (based on safety, tolerability, PK, 
pharmacodynamic, and efficacy data, and recommendations from participating investigators). Details 
of this procedure and the process for communication with investigators are provided in Section 6.3.3. 
For the Phase 2 expansion (approximately n=150), an IDMC will review the safety data on an ongoing 
basis. In addition, a benefit-risk assessment involving review of efficacy and safety data will take place 
once approximately 75 evaluable patients  have been treated/followed for at least six months. The 
primary endpoint of ORR, as assessed by the ICR, will be summarised with 95% confidence intervals 
(Clopper Pearson method).  ORR based on the local radiological assessment will be summarised as a 
sensitivity analysis.   Duration of response and other secondary efficacy endpoints will be described. 
Further details will be provided in the SAP.  
 
Independent Data Monitoring Committee  
An IDMC will be established to provide oversight of safety and efficacy considerations in the Phase 2 
expansion portion of this study. The IDMC will act in an advisory capacity and make recommendations 
regarding steps to ensure both subject safety and the ethical integrity of the trial. The voting members 
of the committee are external to Immunocore, and will not otherwise be involved with the trial. The 
IDMC will include 3 clinicians experienced in oncology/melanoma and 1 statistician. Specific details 
regarding IDMC responsibilities, governance, and documentation will be described in a separate 
charter that is reviewed and approved by the IDMC members. Immunocore has primary responsibility 
for design and conduct of the study. 
The IDMC will monitor trial safety approximately every 4 months, or at a frequency described in the 
IDMC charter. In addition, they will perform a benefit-risk assessment by reviewing both efficacy and 
safety data after approximately 75 evaluable patients in the expansion phase have been 
treated/followed for at least 6 months.  
Following each IDMC meeting, the IDMC will provide recommendations to the Sponsor on any changes 
that may be needed to the future conduct of the study or if the study should continue as planned. 


 
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 Sample Size Calculation 
 Phase 1 Dose Escalation Cohorts 
Cohorts of 3 to 6 evaluable patients will be enrolled in the dose-escalation part including at least 6 
patients at the MTD or RP2D in the RP2D-IE level, as described in Section 6.3. Multiple cohorts may be 
sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 patients may be enrolled at 
any dose level below the estimated MTD/RP2D-IE for further elaboration of safety and PK parameters 
as required.  
 Phase 2 Dose Expansion Cohorts  
The Phase 2 expansion cohorts of approximately 150 patients,including a minimum of 120 patients for 
RECIST evaluation, will provide a substantive dataset of safety, tolerability, and efficacy in uniform 
patient populations. Patients will be enrolled into 2 cohorts as described in Section 3.2: 
The primary analysis of the Phase 2 expansion will focus on the overall Phase 2 population. With 120 
patients and an observed ORR of 10% or more, the precision around the estimation of ORR as assessed 
by 95% confidence intervals will be 5.3% to 16.8%. The study will also provide an adequate number of 
patients in which to assess the safety and tolerability of the RP2D-IE. For example, for AEs of interest, 
if 0 AEs are observed in a cohort of 120 patients, there will be 95% confidence that the true event rate 
is less than 3%. For 150 patents there will be 95% confidence that the true event rate is less than 2.4%.  
In addition, the Phase 2 expansion data will provide an assessment of whether OS may exceed that 
achieved with currently available therapies, 
 
  
An IDMC will review safety data on an ongoing basis (approximately every 4 months) in conjunction 
with a review of safety data from the ongoing randomized study (IMCgp100-202). An interim review 
of both efficacy and safety data from the Phase 2 expansion will be performed by the IDMC after 
approximately 75 evaluable patients have been treated/followed for at least 6 months to enable an 
overall assessment of risk versus benefit. 
 


 
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10 DATA HANDLING AND MANAGEMENT 
 Data Confidentiality 
Information about study patients will be kept confidential and managed under the applicable laws and 
regulations. Those regulations require a signed patient authorization informing the patient of the 
protected health information that will be collected and the use or disclosure of that information. If 
the patient revokes authorization to collect or use this information, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of patient authorization. To 
protect the health information of study patients, access to the data collection system will be controlled 
by a sequence of individual user identification codes and passwords that are made available only to 
authorized trained personnel. 
 Site Monitoring 
Before study initiation at trial sites, Sponsor and/or CRO study team members will review the protocol 
and eCRFs with the investigators and the site study staff. During the study, the field monitor will visit 
the site regularly to check the completeness of patient records, the accuracy of entries on the eCRFs, 
the adherence to the protocol to good clinical practice, the progress of enrollment, and to ensure that 
study treatments are being stored, dispensed, and accounted for according to specifications. Key 
study personnel must be available to assist the field monitor during these visits. The investigator must 
assure that the site monitor is allowed access to all study files, including all site medical records, case 
and visit notes and laboratory reports.   
 Data Collection 
The investigator is required to maintain source documents for each patient in the study, consisting of 
case and visit notes (site medical records), containing demographic and medical information, 
laboratory data, ECGs, and the results of any other tests or assessments. All information recorded in 
the eCRF must be traceable to source documents in the patient's file. The investigator must also keep 
the original signed ICF, with 1 signed copy given to the patient. 
This study will use an electronic data capture (EDC) system and the principal investigator and site study 
staff will enter the data required by the protocol into the eCRF. The eCRF have been built using fully 
validated secure web-enabled software that conforms to 21 CFR Part 11 requirements. The principal 
investigator and all identified site staff will not be given access to the EDC system until they have been 
trained. The principal investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. Field monitors will 
review the eCRF data entries and assist site personnel with any required corrections or additions. 
Tissue samples obtained during the study (e.g., tumor, blood for PK or other analyses) will be collected 
from the investigator sites and analyzed by Immunocore laboratories, contracted central laboratories, 
or local laboratories. Radiological assessments will be reviewed retrospectively in a central repository 
as described. Field monitors will review the eCRF and laboratory paper requisition forms for accuracy 
and completeness and instruct site personnel to make any required corrections or additions. One copy 
of the requisition form will be forwarded to each analytical laboratory with the respective sample by 
the site staff and 1 copy will be retained at the investigational site. 


 
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 Database Management 
Sponsor clinical study personnel and trial field monitors will review the eCRF data entries and assist 
site personnel with any required corrections or additions. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values and 
sent to the investigational site via the EDC system.  
Concomitant treatment and prior medication data in the database will be coded using the WHO Drug 
Reference List, based on the Anatomical Therapeutic Chemical classification. Medical history, current 
medical conditions and AEs in the database will be coded using the Medical Dictionary for Regulatory 
Activities terminology. After database lock, the investigator will receive a CD-ROM of the patient data 
for archiving at the investigational site. 


 
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11 ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
 Regulatory and Ethical Compliance 
This clinical study was designed, shall be implemented and reported in accordance with the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practice E6 (R2), with applicable local regulations 
(including European Directive 2001/20/EC and Unites States Code of Federal Regulations, CFR Title 
21), and with the ethical principles laid down in the Declaration of Helsinki. 
 Responsibilities of the Investigator and Institutional Review Board/Independent 
Ethics Committee/Research Ethics Board 
The protocol and the proposed ICF must be reviewed and approved by a properly constituted IRB or 
IEC or Research Ethics Board (REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to field monitors, auditors, IQVIA Clinical Quality Assurance representatives, 
designated agents of Sponsor, the IRB or IEC or REB and regulatory authorities as required. 
 Informed Consent Procedures 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator and under the Investigator's responsibility, should fully inform the patient of all pertinent 
aspects of the Clinical Trial. All participants should be informed to the fullest extent possible about the 
study, both verbally and in written language and terms they are able to understand. Eligible patients 
may only be included in the study after providing written (witnessed, where required by law or 
regulation) IRB/IEC/REB-approved informed consent which documents their authorization, or if the 
patient is incapable of doing so, after such consent has been provided by a legally 
acceptable/authorized representative of the patient. In cases where the patient’s representative gives 
consent, the patient should be informed about the study to the extent possible given his/her level of 
understanding. If the patient is capable of doing so, he or she should indicate assent by personally 
signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures; the 1 exception 
to this note are radiologic assessments performed before Screening within the specified window. A 
copy of the signed and dated written ICF will be provided to the patient and/or legal representative, 
where appropriate. The process of obtaining informed consent should be documented in the patient 
source documents. The date when a patient’s informed consent was actually obtained will be captured 
in the eCRF. 
The ICF used by the Investigator for obtaining the patient's informed consent must be reviewed and 
approved by the Sponsor prior to submission to the appropriate Ethics Committee (IRB/IEC) for 
approval/favorable opinion.  


 
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 Discontinuation of the Study 
The Sponsor reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 3.6. 
 Publication of Study Protocol and Results 
The Sponsor will publish the key design elements of this protocol in a publicly accessible database 
(clinicaltrials.gov). At the time of study and clinical study report completion, the results of this study 
will be either submitted for publication and/or posted in a publicly accessible database. 
 Study Documentation, Record Keeping, and Retention of Documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 (R2) Good Clinical Practice, and regulatory and institutional 
requirements for the protection of confidentiality of patients. Each site will permit authorized 
representatives of the Sponsor and regulatory agencies to examine any clinical records for the 
purposes of quality assurance reviews, audits and evaluation of the study safety and progress. Source 
data are all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
Principal Investigator. The study eCRF is the primary data collection instrument for the study. The 
investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported 
in the CRFs and all other required reports. Data reported on the CRF, that are derived from source 
documents, should be consistent with the source documents or the discrepancies should be explained. 
All data requested on the CRF must be recorded.  
The investigator should maintain the trial documents as specified in Essential Documents for the 
Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable regulations and guidelines. 
The investigator should take measures to prevent accidental or premature destruction of these 
documents. Essential documents should be retained for a period of not less than 15 years from the 
completion of the Clinical Trial unless Sponsor provides written permission to dispose of them or, 
requires their retention for an additional period of time because of applicable laws, regulations and 
guidelines. 
 Confidentiality of Study Documents and Patient Records 
The investigator must ensure anonymity of the patients; patients must not be identified by names in 
any documents submitted to Immunocore or the CRO. Signed ICFs and patient enrollment log must 
be kept strictly confidential to enable patient identification at the site. 
 Audits and Inspections 
Source data and all trial documents must be available to inspections by the Sponsor, the CRO, or 
designee or Health Authorities. 


 
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 Financial Disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the treatment 
or evaluation of patients at the site, prior to study start.


 
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13 APPENDICES 
 Appendix 1:  Guidelines for Modified RECISTv.1.1 Criteria  
These guidelines are based on the original RECIST for tumor responses (Therasse, 2000), and the revised 
RECIST v.1.1 guidelines (Eisenhauer, 2009). The efficacy assessments and definitions of best response and 
PD for the purposes of the primary endpoint of ORR described in this study are based on the RECIST v.1.1 
criteria.  
 Efficacy Assessments 
Tumor evaluations for the purposes of the primary endpoint are made based on RECIST criteria (Therasse, 
2000), New Guidelines to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer 
Institute, Volume 92; pages 205–216 and revised RECIST guidelines (version 1.1) (Eisenhauer, 2009). 
 Definitions of Measurable and Non-measurable Disease 
Measurable disease represents the presence of at least 1 measurable nodal or non-nodal lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
Measurable lesions (both nodal and non-nodal):  Measurable non-nodal — the minimum size of a 
measurable non-nodal target lesion at Baseline should be no less than double the slice thickness or 10mm 
whichever is greater — e.g., the minimum non-nodal lesion size for CT/MRI with 5 mm cuts will be 10 mm. 
Lytic bone lesions or mixed lesions with identifiable soft tissue components that can be evaluated by 
CT/MRI can be considered as measurable lesions, if the soft tissue component meets the definition of 
measurability. Measurable nodal lesions (i.e., lymph nodes) — Lymph nodes  15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring  10 mm and < 15 mm are considered 
non-measurable. Lymph nodes smaller than 10 mm in short axis at Baseline, regardless of the slice 
thickness, are normal and not considered indicative of disease. 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. Simple cysts with non-enhancing walls and low CT 
density are not considered malignant lesions unless proven by biopsy. 
Non-measurable lesions:  All other lesions are considered non-measurable, including small lesions (e.g., 
longest diameter < 10 mm with CT/MRI or pathological lymph nodes with  10 to < 15 mm short axis), as 
well as truly non-measurable lesions e.g., blastic bone lesions, ascites, pleural/pericardial effusion, and 
inflammatory breast disease. 


 
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 Methods of Tumor Measurement  
All measurements should be taken and recorded in metric notation (mm), using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and never 
more than 4 weeks before the beginning of the treatment. Imaging-based evaluation is preferred to 
evaluation by clinical examination when both methods have been used to assess the antitumor effect of 
a treatment. For optimal evaluation of patients, the same methods of assessment and technique should 
be used to assess each reported lesion at Baseline and during Follow-up. Contrast-enhanced CT of chest, 
abdomen and pelvis should preferably be performed using a 5 mm slice thickness. If a patient is known to 
have a medical contraindication to CT contrast or develops a contraindication during the trial, the 
following change in imaging modality will be accepted for follow up:  a non-contrast CT of chest (MRI not 
recommended due to respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis. 
Other Tumor Response Considerations 
MRI for liver disease:  In some instances, liver disease in patients with UM can be imaged more effectively 
with MRI.  
Fluorodeoxyglucose-positron emission tomography, Endoscopy and Laparoscopy:  The utilization of PET 
imaging, endoscopy and laparoscopy for objective tumor evaluation has not yet been fully and widely 
validated. The utilization of such techniques for objective tumor response should be restricted to 
validation purposes in specialized centers; however, such techniques can be useful in confirming complete 
pathological response when biopsies are obtained. 
Cytology and histology:  Cytology and histology can be used to differentiate between PR and CR in rare 
cases (i.e., after treatment to differentiate between residual benign lesions and residual malignant lesions 
in tumor types such as germ cell tumors).  
Clinical examination:  Clinical lesions will only be considered measurable when they are superficial (i.e., 
skin nodules and palpable lymph nodes). For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. Clinical disease 
progression is acceptable and wherever possible should be confirmed by imaging studies.  
 Definitions of Target and Non-target Lesions 
For the evaluation of lesions at Baseline and throughout the study, the lesions are classified at Baseline as 
either target or non-target lesions: 
Target Lesions:  All measurable lesions (nodal and non-nodal) up to a maximum of 5 lesions in total (and 
a maximum of 2 lesions per organ), representative of all involved organs should be identified as target 
lesions and recorded and measured at Baseline. Target lesions should be selected based on size (lesions 
with the longest diameter) and suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  


 
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Each target lesion must be uniquely and sequentially numbered on the eCRF (even if it resides in the same 
organ). A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions will 
be calculated and reported as the baseline sum of diameters. The baseline sum of diameters will be used 
as reference by which to characterize the objective tumor response. Each target lesion identified at 
Baseline must be followed at each subsequent evaluation and documented on eCRF.  
Non-target Lesions:  All other lesions are considered non-target lesions, i.e., lesions not fulfilling the 
criteria for target lesions at Baseline. Presence or absence or worsening of non-target lesions should be 
assessed throughout the study; measurements of these lesions are not required. Multiple non-target 
lesions involved in the same organ can be assessed as a group and recorded as a single item (i.e., multiple 
liver metastases). Each non-target lesion identified at Baseline must be followed at each subsequent 
evaluation and documented on eCRF. 
 Determination of Target Lesion Response 
Table 13-1 
Response Criteria for Target Lesions 
Response Criteria 
Evaluation of Target Lesions 
Complete Response 
Disappearance of all non-nodal target lesions. In addition, any pathological 
lymph nodes assigned as target lesions must have a reduction in short axis 
to < 10 mm1 
Partial Response 
At least a 30% decrease in the sum of diameter of all target lesions, taking 
as reference the baseline sum of diameters 
Progressive Disease 
At least a 20% increase in the sum of diameter of all measured target 
lesions, taking as reference the smallest sum of diameter of all target lesions 
recorded at or after Baseline. In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm2 
Stable Disease 
Neither sufficient shrinkage to qualify for partial response or complete 
response nor an increase in lesions which would qualify for progressive 
disease 
1. Sum of diameters for complete response may not be 0 when nodal lesions are part of target lesions. 
2. Following an initial complete response, progressive disease cannot be assigned if all non-nodal target 
lesions are still not present and all nodal lesions are < 10 mm in size. In this case, the target lesion 
response is complete response. 
Notes on Target Lesion Response 
 
Lesions split:  In some circumstances, disease that is measurable as a target lesion at Baseline and 
appears to be 1 mass can split to become 2 or more smaller sub-lesions. When this occurs, the 
diameters (long axis — non-nodal lesion, short axis - nodal lesions) of the 2 split lesions should be 
added together and the sum recorded in the diameter field on the case report form under the 
original lesion number. This value will be included in the sum of diameters when deriving target 


 
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lesion response. The individual split lesions will not be considered as new lesions, and will not 
automatically trigger a PD designation 
 
Lesions coalesced:  Conversely, it is also possible that 2 or more lesions which were distinctly 
separate at Baseline become confluent at subsequent visits. When this occurs a plane between 
the original lesions may be maintained that would aid in obtaining diameter measurements of 
each individual lesion. If the lesions have truly coalesced such that they are no longer separable, 
the maximal diameters (long axis — non-nodal lesion, short axis - nodal lesions) of the “merged 
lesion” should be used when calculating the sum of diameters for target lesions. On the case 
report form, the diameter of the “merged lesion” should be recorded for the size of 1 of the 
original lesions while a size of “0”mm should be entered for the remaining lesion numbers which 
have coalesced 
 Determination of Non-target Lesion Response 
Table 13-2 
Response Criteria for Non-target Lesions 
Response Criteria 
Evaluation of Non-target Lesions 
Complete Response 
Disappearance of all non-target lesions. In addition, all lymph 
nodes assigned non-target lesions must be non-pathological in 
size (< 10 mm short axis) 
Progressive Disease 
Unequivocal progression of existing non-target lesions1 
Non-complete response/  
Non-progressive disease 
Neither complete response nor progressive disease 
1. Although a clear progression of non-target lesions only is exceptional, in such circumstances, the 
opinion of the treating physician does prevail and the progression status should be confirmed later on by 
the central review. 
Non-target Lesion Response 
 
The response for non-target lesions is CR only if all non-target non-nodal lesions which were 
evaluated at Baseline are now all absent and with all non-target nodal lesions returned to normal 
size (i.e., < 10 mm). If any of the non-target lesions are still present, or there are any abnormal 
nodal lesions (i.e.,  10 mm) the response can only be ‘Non-CR/Non-PD’  
 
Unequivocal progression:  To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such that, 
even in presence of CR, PR, or stable disease (SD) in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. In order for a PD to be assigned on the 
basis of non-target lesions, the increase in the extent of the disease must be substantial even in 
cases where there is no measurable disease at Baseline  


 
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New Lesions 
The appearance of a new lesion is always associated with PD and has to be recorded as a new lesion in 
the eCRF. 
 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the first observation 
of the lesion 
 
If new disease is observed in a region which was not scanned at Baseline or where the particular 
baseline scan is not available for some reason, then this should be considered PD  
 
A lymph node is considered as a “new lesion” and, therefore, indicative of PD if the short axis 
increases in size to  10 mm for the first time in the study plus 5 mm absolute increase 
 Evaluation of Overall Lesion Response 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in 
Table 13-3. 
 
Table 13-3 
Overall Lesion Response at Each Assessment 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Lesion Response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR1 
SD 
Non-PD 
No 
SD1, 2 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. 
1. This overall lesion response also applies when there are no non-target lesions identified at Baseline.
2. Once confirmed PR was achieved, all these assessments are considered PR. 
References:   
Eisenhauer EA, Therasse P, Bogaerts J. New response evaluation criteria in solid tumours:  revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–247 
Therasse P, Arbuck SG, Eisenhauer EA. New guidelines to evaluate the response to treatment in solid
tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the
United States, National Cancer Institute of Canada. Natl Cancer Inst. 2000;92(3):205–216. 


 
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 Appendix 2:  Modified Immune-related RECIST Comparison to RECIST v.1.1  
The response criteria set known as irRECIST) (Bohnsack, 2014) is an adaptation of the immune-related 
response criteria (irRC) (Wolchok, 2009; Nishino, 2013) that is based upon World Health Organization 
criteria for tumor response evaluation utilizing bi-dimensional criteria. Nishino, et al, demonstrated that 
the irRC could be implemented using unidimensional criteria (Nishino, 2013). Some further modifications 
were proposed to further align the immune-related criteria with RECISTv.1.1 and this approach has been 
named irRECIST criteria (Bohnsack, 2014).  
A further modification to the guidance is implemented in this study, such that for patients who continue 
IMCgp100 therapy beyond initial PD, unequivocal, confirmed PD is defined as an additional 20% increase 
in tumor burden (sum of diameters of both target and measurable new lesions) or unequivocal 
progression of NTLs and/or new non-measurable disease from the initial PD assessment per RECISTv1.1 
rather than from the nadir. This modification is based on early observations of prolonged disease 
stabilization with IMCgp100 beyond progression in the dose escalation cohorts of this study (Sato, 2017). 
This definition is referred to in the protocol as irPD per modified irRECIST.  
The key modifications between the RECISTv.1.1 assessments and modified irRECIST assessments are 
described below.  
 Key Changes from RECIST v.1.1 to Modified irRECIST Criteria  
13.2.1.1 
Total Measured Tumor Burden 
Baseline-selected target lesions and new measurable lesions should NOT be assessed separately but 
combined for the total tumor burden. Measurements of those lesions should be combined into the total 
measured tumor burden (TMTB), and 1 combined assessment provided. 
13.2.1.2 
New Measurable Lesions 
According to irRC (Wolchok, 2009), a measurable new lesion has to be at least 5 mm × 5 mm to be selected 
as an index lesion; for bi-dimensional measurements this threshold was acceptable. In irRECIST, criteria 
for unidimensional lesion measurement apply to both target and new measurable lesions:  a minimum 10 
mm in the longest diameter for non-nodal lesions, and a minimum 15 mm in short axis for lymph nodes 
(Bohnsack, 2014). Smaller lesions contribute to the non-target or new non-measurable tumor burden, but 
are not measured. 
13.2.1.3 
Non-target Lesions  
In alignment with RECIST v.1.1, baseline selected non-target lesions can never convert to measurable 
lesions, not even if they increase in size at subsequent timepoints and become measurable. Only true new 
lesions measurable at first appearance can contribute to the TMTB for irRECIST. For example:  A patient 
has multiple lung metastases, all smaller than 10 mm and selected as non-target lesions at Baseline. If, at 


 
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a subsequent timepoint some of these non-target lesions increase and become > 10 mm, and 1 new lesion 
>10 mm appears, only the new measurable lesion will contribute to the TMTB, and not the non-target 
lesions that increased in size from baseline.  
13.2.1.4 
Immune-related Progressive Disease Based on Non-target Lesions  
Unlike irRC that neglect non-target lesions for the assessment of irPD, in irRECIST a substantial and 
unequivocal increase of non-target lesions is indicative of progression. 
13.2.1.5 
Immune-related Progressive Disease Based on New Non-measurable Lesions 
According to irRECIST, the reviewer may assign irPD for the patient with multiple new non-measurable 
lesions if they are considered to be a sign of unequivocal, massive worsening.  
13.2.1.6 
Immune-related Progressive Disease Confirmation per modified irRECIST 
In this study, confirmed irPD is defined as an additional 20% increase in the total tumor burden (target 
lesions and any new measurable lesions) and/or increased/further unequivocal progression of NTLs 
and/or new non measurable lesions from the initial assessment of PD per RECISTv.1.1. Confirmation of 
irPD progression should occur at least 4 weeks after the initial assessment of RECISTv.1.1 PD.Further 
confirmation of irPD after its occurrence is not required, but may be done at Investigator discretion. 
 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 1 of 131
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
IMCGP100-102 
 
A PHASE 1/2 OPEN-LABEL, MULTI-CENTER STUDY OF THE SAFETY AND EFFICACY OF 
IMCGP100 USING THE INTRA-PATIENT ESCALATION DOSING REGIMEN IN PATIENTS WITH 
ADVANCED UVEAL MELANOMA 
 
 
 
 
 
AUTHOR: 
 
 
VERSION NUMBER AND DATE: V4.0 FINAL, 28MAY2020 
 
 
 
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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V4.0 Final (Dated 28MAY2020) for Protocol IMCgp100-102. 
 
Name 
Signature 
Date 
Author: 
 
 
 
Position/Company: 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 

Name 
Signature 
Date 
Approved By: 
 
 
Position/Company: 
 
Approved By: 
 
 
Position/Company: 
 
Approved By: 
 
 
Position/Company: 
 
 
Approved By: 
 
Position/Company: 
  Note the output templates will be signed of separately to the Statistical Analysis Plan.  


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 3 of 131
 MODIFICATION HISTORY 

Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 DRAFT 
13MAY2016 
 
Not Applicable – First draft version sent to 
Immunocore
2.0 DRAFT 
13JUL2016 
 
Final updates following Immunocore first 
draft review. 
3.0 DRAFT 
09AUG2016 
 
 
Further updates following Immunocore 
second draft review. 
1.0 FINAL 
25AUG2016 
 
Finalization of first version. 
2.0 FINAL 
01MAY2019 
 
Updates to align with Protocol version 8 
(Amendment 7), including major changes to 
the Efficacy, Safety, and Exploratory 
sections. 
3.0 FINAL 
20MAY2020 
 
Updates included but not limited to:  
x
Changes to exploratory efficacy, 
x
Additional subgroups in Section 7.5.  
x
Further details on: 
o
Concomitant medications 
o
Adverse events of special 
interest  
o
Exposure  
o
Vital signs 
o
Pharmacokinetics 
o
Immunogenicity 
o
Patient reported outcomes  
4.0 FINAL 
28MAY2020 
 
Minor formatting updates.  


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
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TABLE OF CONTENTS 
1. INTRODUCTION ............................................................................................................................. 11 
2. STUDY OBJECTIVES ...................................................................................................................... 11 
2.1. 
Primary Objectives ................................................................................................................................. 11 
2.2. 
Secondary Objectives ............................................................................................................................. 11 
2.3. 
Exploratory Objectives ........................................................................................................................... 12 
3. STUDY DESIGN ............................................................................................................................... 13 
3.1. 
General Description ............................................................................................................................... 13 
3.2. 
Schedule of Events ................................................................................................................................. 15 
3.3. 
Changes to Analysis from Protocol ......................................................................................................... 16 
4. PLANNED ANALYSES .................................................................................................................... 17 
4.1. 
Independent Data Monitoring Committee ............................................................................................. 19 
4.1.1. 
Regular Safety Reviews .............................................................................................................................19 
4.1.2. 
Interim Analysis to Assess Benefit Risk .....................................................................................................19 
5. ANALYSIS SETS .............................................................................................................................. 20 
5.1. 
All Patients Enrolled Set ......................................................................................................................... 20 
5.2. 
Full Analysis Set ..................................................................................................................................... 20 
5.3. 
Per-Protocol Set ..................................................................................................................................... 20 
5.4. 
Safety Set ............................................................................................................................................... 21 


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PROTOCOL IMCgp100-102 
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6. GENERAL CONSIDERATIONS ..................................................................................................... 22 
6.1. 
Reference Start Date and Study Day ...................................................................................................... 22 
6.2. 
Baseline ................................................................................................................................................. 22 
6.3. 
Retests, Unscheduled Visits and End of Treatment Data ........................................................................ 23 
6.4. 
Windowing Conventions ........................................................................................................................ 23 
6.5. 
Statistical Tests ...................................................................................................................................... 23 
6.6. 
Common Calculations ............................................................................................................................ 23 
6.7. 
Software Version ................................................................................................................................... 24 
7. STATISTICAL CONSIDERATIONS ............................................................................................. 24 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses ...................................................... 24 
7.2. 
Multicenter Studies ............................................................................................................................... 24 
7.3. 
Missing Data .......................................................................................................................................... 24 
7.4. 
Multiple Comparisons/ Multiplicity ....................................................................................................... 25 
7.5. 
Examination of Subgroups ..................................................................................................................... 25 
8. OUTPUT PRESENTATIONS ......................................................................................................... 26 
9. DISPOSITION AND WITHDRAWALS ....................................................................................... 26 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................... 27 
10.1. 
Derivations ............................................................................................................................................ 29 


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PROTOCOL IMCgp100-102 
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11. 
SURGICAL AND MEDICAL HISTORY ..................................................................................... 30 
12. 
CONCOMITANT MEDICATIONS ............................................................................................. 30 
12.1. 
Prohibited Concomitant Medications/Therapies ................................................................................... 31 
12.2. 
Anti-Neoplastic Therapies Post Treatment ............................................................................................ 31 
13. 
STUDY DRUG EXPOSURE ........................................................................................................ 32 
13.1. 
Study Drug Exposure Derivations ........................................................................................................... 32 
13.1.1. 
Missing Data Methods For Study Exposure Variables ..............................................................................38 
14. 
EFFICACY OUTCOMES .............................................................................................................. 39 
14.1. 
Primary Efficacy ..................................................................................................................................... 39 
14.1.1. 
Primary Efficacy Variables & Derivations..................................................................................................39 
 
Phase 1 dose escalation ....................................................................................................................39 
 
Phase 2 dose expansion ....................................................................................................................39 
14.1.2. 
Derivation of Best overall Response using RECIST v1.1 Criteria ...............................................................39 
14.1.3. 
Confirmation of Objective Response using RECIST v1.1 Criteria ..............................................................41 
14.1.4. 
Missing Data Methods for Primary Efficacy Variable ...............................................................................42 
14.1.5. 
Primary Analysis of Primary Efficacy Variables .........................................................................................42 
 
Phase 1 dose escalation ....................................................................................................................42 
 
Phase 2 dose expansion ....................................................................................................................42 
14.1.6. 
Sensitivity Analysis of Primary Efficacy Variable .......................................................................................42 
 
Phase 2 dose expansion – Repeat using Per-Protocol Set ................................................................42 
14.2. 
Secondary Efficacy ................................................................................................................................. 43 
14.2.1. 
Secondary Efficacy Variables & Derivations .............................................................................................43 
 
BOR and ORR using RECIST v1.1 .......................................................................................................44 
 
Progression Free Survival ..................................................................................................................44 
 
Overall Survival .................................................................................................................................45 
 
Duration of Response .......................................................................................................................46 
 
Time to Response .............................................................................................................................46 
 
Best Percent Change in Baseline of Tumor Size ................................................................................46 
 
Disease Control Rate .........................................................................................................................47 


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Rate and Duration of Minor Response .............................................................................................47 
14.2.2. 
Missing Data Methods for Secondary Efficacy Variables ..........................................................................48 
14.2.3. 
Analysis of Secondary Efficacy Variables ..................................................................................................48 
 
BOR and ORR using RECIST v1.1 .......................................................................................................48 
 
Concordance between Investigator assessment and ICR of BOR for RECIST v1.1 ............................48 
 
Progression Free Survival ..................................................................................................................48 
 
Overall Survival .................................................................................................................................49 
 
Duration of Response .......................................................................................................................49 
 
Time to Response .............................................................................................................................49 
 
Change in Tumor Size .......................................................................................................................49 
 
Disease Control Rate .........................................................................................................................50 
 
Rate and Duration of Minor Response .............................................................................................50 
 
Subgroup Analyses of Efficacy Variables ..........................................................................................50 
 
Swimmer Plot of Tumor Data ...........................................................................................................50 
14.3. 
Exploratory efficacy ............................................................................................................................... 51 
14.3.1. 
Exploratory Efficacy Variables & Derivations ...........................................................................................51 
 
Tumor assessments using irRECIST by ICR or Modified irRECIST/irRC Criteria .................................51 
 
Derivation of Best overall Response using irRECIST by ICR or Modified irRECIST/irRC Criteria .......53 
 
Confirmation of Overall Response Using irRECIST by ICR or Modified irRECIST/irRC Criteria ..........55 
14.3.2. 
Missing Data Methods for Exploratory Efficacy Variables ........................................................................56 
14.3.3. 
Analysis of Exploratory Efficacy Variables ................................................................................................57 
 
BOR and Duration of Treatment Post RECIST-Progression (PD) .......................................................57 
15. 
SAFETY OUTCOMES .................................................................................................................. 59 
15.1. 
Dose Limiting Toxicities ......................................................................................................................... 59 
15.2. 
Adverse Events ...................................................................................................................................... 60 
15.2.1. 
All TEAEs ...................................................................................................................................................62 
 
Severity .............................................................................................................................................62 
 
Relationship to Study Drug (IMCgp100) ...........................................................................................62 
15.2.2. 
TEAEs Leading to Dose Interruption .........................................................................................................62 
15.2.3. 
TEAEs Leading to Discontinuation of Study Drug .....................................................................................62 
15.2.4. 
Serious Adverse Events .............................................................................................................................63 
15.2.5. 
Adverse Events Leading to Death .............................................................................................................63 
15.2.6. 
Adverse Events of Special Interest ...........................................................................................................63 
15.2.7. 
Adverse Events Beyond Disease Progression ...........................................................................................64 


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15.3. 
Deaths ................................................................................................................................................... 64 
15.4. 
Laboratory Evaluations .......................................................................................................................... 65 
15.4.1. 
Laboratory Specific Derivations ................................................................................................................66 
15.4.2. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ..............................................................67 
15.4.3. 
NCI CTCAE Grading for Laboratory Data ...................................................................................................68 
15.5. 
ECG Evaluations ..................................................................................................................................... 71 
15.5.1. 
ECG Specific Derivations ...........................................................................................................................72 
15.5.2. 
ECG Markedly Abnormal Criteria ..............................................................................................................72 
15.6. 
Vital Signs .............................................................................................................................................. 74 
15.6.1. 
Vital Signs Specific Derivations .................................................................................................................75 
15.6.2. 
Vital Signs Markedly Abnormal Criteria ....................................................................................................75 
15.7. 
Physical Examination ............................................................................................................................. 77 
15.8. 
Other Safety Assessments ..................................................................................................................... 77 
15.8.1. 
ECOG Performance Status ........................................................................................................................77 
16. 
PHARMACOKINETICS ............................................................................................................... 78 
16.1.1. 
PK Variables & Derivations .......................................................................................................................78 
16.1.2. 
Analysis of PK ............................................................................................................................................79 
16.1.3. 
Missing Data Methods for Pharmacokinetic Data ....................................................................................80 
16.1.4. 
Reporting of Pharmacokinetic Data ..........................................................................................................80 
17. 
IMMUNOGENICITY .................................................................................................................... 82 
17.1.1. 
ADA Variables & Derivations ....................................................................................................................82 
17.1.2. 
Missing Data Methods for ADA ................................................................................................................85 
17.1.3. 
Analysis of ADA .........................................................................................................................................85 
 
Patient ADA Status ............................................................................................................................85 
 
Study ADA Summary .........................................................................................................................86 
18. 
EXPLORATORY OBJECTIVES .................................................................................................. 87 
18.1. 
 ............................................................................................................................ 87 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 9 of 131
18.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ..................................................................................................93 
18.3. 
 
 
 ................................................................................................................................................94 
18.4. 
............................................................................................................................................ 94 
19. 
DATA NOT SUMMARIZED OR PRESENTED ....................................................................... 95 
20. 
REFERENCES ............................................................................................................................... 96 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS ............................................... 97 
IQVIA Output Conventions .................................................................................................................................... 97 
Dates & Times ..................................................................................................................................................... 105 
Spelling Format ................................................................................................................................................... 105 
Presentation of Treatment Groups ..................................................................................................................... 105 
Presentation of Visits .......................................................................................................................................... 107 
Listings 107 
APPENDIX 2. PARTIAL DATE CONVENTIONS ........................................................................... 109 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
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Algorithm for Treatment Emergence of Adverse Events: .................................................................................... 109 
Algorithm for Prior / Concomitant Medications: ................................................................................................. 112 
Algorithm for Anti-Neoplastic Therapies Post Treatment Discontinuation: ......................................................... 114 
APPENDIX 3.
 ................................................................. 116 
APPENDIX 4.
 ................................................... 116 
APPENDIX 5. DATA CUT-OFF APPROACH FOR SDTM DATA ................................................ 117 
APPENDIX 6. PROCESS FOR CATEGORIZING SKIN TOXICITIES ASSOCIATED WITH 
TEBENTAFUSP, INCLUDING RASH ............................................................................................... 130 
 
 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 11 of 131
1.INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy, safety, 
pharmacokinetics (PK) and exploratory endpoints (
 
) data for 
Protocol IMCgp100-102. It describes the data to be summarized and analyzed, including specifics of the statistical 
analyses to be performed.  Details of analyses relating to other study objectives and endpoints will be described in 
separate documents. 
This statistical analysis plan (SAP) is based on Protocol Amendment 7.0 (version 8.0), dated 26th November 2018 
and Administrative Letter dated 22nd April 2020.  
2.STUDY OBJECTIVES 
2.1.
PRIMARY OBJECTIVES 
The primary objectives are: 
x
Phase 1 Dose Escalation:  The primary objective is to identify the maximum tolerated dose (MTD) 
and/or the recommended Phase 2 dose (RP2D) of IMCgp100 in the intra-patient dose escalation 
regimen. 
x
Phase 2 Dose Expansion:  The primary objective is to estimate the objective response rate (ORR) by 
independent central review (ICR) based on Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST v1.1) in patients with metastatic Uveal Melanoma (mUM) who are treated with the 
recommended Phase 2 dose intra-patient escalation (RP2D-IE) of IMCgp100.  
2.2.
SECONDARY OBJECTIVES 
The secondary objectives are: 
x
To characterize the safety and tolerability of IMCgp100 in the intra-patient dose escalation regimen 
x
To characterize the PK profile of single-agent IMCgp100 in the intra-patient dose escalation regimen 
x
To assess the anti-tumor efficacy of IMCgp100 with the parameters of objective response rate (ORR) 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 12 of 131
(Phase 1), overall survival (OS), progression free survival (PFS), disease control rate ≥ 24 weeks and 
the duration of response (DOR) 
x
To evaluate the incidence of anti-IMCgp100 antibody formation following multiple infusions of 
IMCgp100 in the intra-patient dose escalation regimen 
x
To determine the rate and duration of minor responses (MinR) (defined as tumor response with a 
10%-29% reduction in the sum of longest diameters (SOLD)) 
2.3.
EXPLORATORY OBJECTIVES 
 
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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 13 of 131
3.STUDY DESIGN 
3.1.
GENERAL DESCRIPTION 
This is a Phase 1/2 study of IMCgp100 administered on a once a week (QW) basis with an intra-patient escalation 
dosing regimen. The intra-patient escalation occurs at the third weekly dose on Cycle 1 Day 15 (C1D15).  
The Phase 1 portion of the study will be a standard 3+3 dose escalation design. Patients in the Phase 1 study will 
receive 2QW doses of IMCgp100 at a dose level below the identified weekly recommended Phase 2 dose (RP2D-
QW, 50mcg flat dose) and then a dose escalation will commence at the third QW dose at C1D15 with the goal to 
achieve a long-term dosing regimen at a dose higher than that identified for the straight weekly dosing regimen 
(i.e. RP2D-QW of 50mcg). The dose escalation will identify the RP2D-IE. 
)LJXUH Figure_3-1 below outlines the dosing schedule for the Phase 1 dose escalation and the Phase 2 
expansion. Note: Enrollment into the Phase 1 dose escalation portion has been completed and RP2D-IE was 
determined to be 68 mcg with 20 mcg given on C1D1, 30 mcg given on C1D8 and then 68 mcg given on C1D15 and 
the same escalated dose level thereafter. The actual doses assessed in the Phase 1 escalation are provided in 
Figure_3-1. The Phase 1 dose escalation had an additional Cohort 4 (intra-patient escalation dose of 68 mcg) as an 
option to evaluate intermediate doses prior to expansion (this is not shown in Figure 3-1).   
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Phase 1 Dose escalation 
 
 
 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 14 of 131
Phase 2 expansion 
 
  
Once the RP2D-IE is determined in the Phase 1 dose escalation then recruitment will begin into the Phase 2 
expansion cohorts. These two cohorts will enrol approximately 150 patients combined.  
x
Cohort A will enrol patients who have experienced disease progression with 1 systemic treatment regimen 
containing a checkpoint inhibitor, including either a CTLA4 inhibitor (ipilimumab or tremelimumab) and/or 
a PD-1/PD-L1 inhibitor. Any prior LDT is acceptable in this cohort.
x
Cohort B will enrol patients who have experienced disease progression with 1 or 2 prior lines of therapy in 
the metastatic or advanced setting including chemotherapy, immunotherapy or targeted therapy. Only a 
single line of local, LDT including chemotherapy, radiotherapy, radiofrequency ablation or embolization is 
allowed. A line of LDT is defined as one modality of treatment that is administered until completion of 
treatment or disease progression. For patients who have received prior LDT, this will count as a line of 
therapy. Prior surgical resection of oligometastatic liver disease is allowed and is not counted as a line of 
LDT. A patient may have discontinued systemic therapy prior to disease progression if the patient 
experienced an adverse reaction that required treatment discontinuation, as per Investigator’s judgment 
and applicable labelling. Prior checkpoint inhibitor therapy is acceptable but not required in this cohort.
These expansion cohorts are designed to further characterize the safety, tolerability, and preliminary PK and anti-
tumor activity of IMCgp100. 
Figure 3-2 outlines the study design. For the purpose of analysis and reporting, patients from cohorts A and B will 
be combined and referred to as the “Phase 2 Expansion” cohort throughout the SAP due to significant overlap 
between the two groups and given this cohort assignments were not prospectively implemented during study 
conduct. Additional details on the Phase 2 Expansion cohorts are provided in Section 3.2 and Section 5.2 of the 
Protocol.  
 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 15 of 131
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The study will consist of the following Periods: Pre-screening, Screening, Treatment Period, 90-day Safety Follow-
up, Disease Progression Follow-up and Survival Follow-up. Further details of these study periods can be found in 
Section 3.3 of the Protocol. 
Treatment will be administered as described until the patient experiences unacceptable toxicity, or the patient 
experiences unequivocal, confirmed Progressive Disease (PD) as defined by modified irRECIST (or modified 
Immune related response criteria (irRC) for patients that discontinued before Protocol version 7). The end of the 
study will be when a minimum of 80% of the patients have completed the follow-up for disease progression or 
discontinued the study for any reason, and all patients have completed treatment and the 90-day Follow-up 
Period, or if the study is terminated early. 
3.2.
SCHEDULE OF EVENTS 
Schedule of events can be found in Section 7.1 of the Protocol in Table 7-1.  
 
 
 
 
 
 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 16 of 131
3.3.
CHANGES TO ANALYSIS FROM PROTOCOL 
The planned changes to the analysis are the following: 
x
A Per-Protocol analysis of the Objective Response Rate (ORR) and duration of response in Phase 2 
dose expansion only will be produced, which differs from the Protocol. 
x
Prior therapy subgroups will be defined as i.) combination of systemic therapy and any LDT, ii.) 
systemic therapy(s) only, and iii.) LDT only. This differs from the Protocol which states only “1 LDT” 
for subgroup levels i.) and iii.). This is necessary for analysis because any number of prior Liver 
Directed Therapies may be taken in Phase 2 Expansion Cohort A. 
x
The denominator in the calculation of the ORR for the Primary Efficacy in Phase 2 will be the total 
number of patients in the Full Analysis Set (FAS), rather than the subset with measurable disease at 
baseline, as stated in the Protocol. 
x
The timing of the interim analysis to assess for benefit risk will be extended to allow the potential of 
at least 9 months follow up.  
x
The timing of the primary analysis will be extended to allow to the potential for at least 12 months 
follow up. 
x
A further analysis (follow-up) may be conducted after the primary analysis if required, to include 
further follow-up time for the existing patients. 
x
Patients in the Phase 1 dose escalation treatment group will not be summarized by dose cohort for 
most efficacy endpoints as stated in the Protocol, and instead all Phase 1 patients will be summarized 
as a total pooled group, i.e. ‘Phase 1 dose escalation cohorts - Total’.  The rationale for this change is 
due to overlapping PK exposure between the dose levels explored in Phase 1. 
x
The immune response endpoint (as assessed by area under the tumor response curve) will not be 
covered in this SAP. The endpoint will not be analyzed as stated in the Protocol under the secondary 
objectives. The Protocol will not be amended for this, but this was noted in an Administrative Letter 
to all investigative sites (dated 22APR2020).  


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 17 of 131
4.PLANNED ANALYSES 
The following analyses will be performed for this study: 
Analysis 
Number 
Analysis Name 
Number of patients*  
Approximate 
Minimum follow-
up 
Purpose 
1 
Interim Analysis† 
Phase 2: 75† 
 
 
9 months 


The interim efficacy 
analysis will focus on 
response rate and 
duration of response (as 
per ICR) as well as 
available PFS and OS 
data. In addition, safety 
data will also be 
reviewed to allow an 
overall assessment of 
benefit risk.  Full details 
can be found in the 
IDMC Charter.
2 
Primary Analysis 
Phase 2: 120 to 150 
12 months 
The primary analysis 
will include all patients 
treated in Phase 2 
with a minimum 
follow up time to 
adequately analyze 
the efficacy and safety 
of IMCgp100. 
Note: will be 
considered a 
secondary analysis if a 
favourable benefit risk 
is determined at the 
interim. 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 18 of 131
Analysis 
Number 
Analysis Name 
Number of patients*  
Approximate 
Minimum follow-
up 
Purpose 
3 
Final Analysis 
Phase 2: 120 to 150 
To be agreed 
following the 
primary analysis.  
Final analysis of key 
outputs (mainly 
overall survival, 
progression free 
survival, duration of 
response and ongoing 
safety) based on final, 
locked data. 
*The timing of each analysis is determined by the number of patients and their follow-up in Phase 2. Phase 1 data 
will be reported for the Interim, Primary and Final Analysis. For the interim analysis, the approximate minimum 
follow-up time of 9 months, is based on 40 weeks (+/- 1 week) and determines the data cut-off date for the interim 
regardless of whether the 75th patient discontinues early. 
†The Independent Data Monitoring Committee (IDMC) will conduct regular safety reviews, in addition to the 
interim analysis. The interim analysis will become the primary analysis if a favourable benefit-risk is determined at 
the interim. If that occurs, then the analysis carried out once 120 to 150 patients have completed approximately 
12 months of follow-up will be considered secondary. 
A data cut-off approach will be applied for the interim and primary analysis. Details of the algorithms applied are 
described in the document Data Cut-off Approach for SDTM Data V6.0 as referenced in APPENDIX 5.  
Following the primary analysis, a decision will be made as to whether further follow up is required or if the study 
will close. At study closure, arrangements will be made to manage any patients ongoing study treatment, or any 
follow up required for safety purposes.  
All Analyses identified in this SAP will be performed by IQVIA Biostatistics following Sponsor Authorization of this 
Statistical Analysis Plan, Database Lock (for the final analysis), and Sponsor Authorization of Analysis Sets, based 
on all patient data up to the follow-up time given in the above table.  
 


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PROTOCOL IMCgp100-102 
Page 19 of 131
4.1.
INDEPENDENT DATA MONITORING COMMITTEE  
An Independent Data Monitoring Committee (IDMC) will be established to provide oversight of safety and efficacy 
considerations in the Phase 2 expansion portion of this study. The IDMC will act in an advisory capacity and make 
recommendations regarding steps to ensure both subject safety and the ethical integrity of the study. The voting 
members of the committee are external to the sponsor and will not otherwise be involved with the study. The 
IDMC will include 2-3 clinicians experienced in oncology/melanoma and 1 statistician. Specific details regarding 
IDMC responsibilities, governance, and documentation will be described in a separate charter that is reviewed and 
approved by the IDMC members.  
The IDMC will perform the regular safety reviews as well as the interim benefit-risk assessment. Following each 
IDMC meeting, the IDMC will provide recommendations to the Sponsor on any changes that may be needed to the 
future conduct of the study or if the study should continue as planned.  
4.1.1.
REGULAR SAFETY REVIEWS 
The IDMC will monitor trial safety approximately every 4 months, or at a frequency described in the IDMC charter. 
Details of the safety data to be reviewed will be agreed between the Sponsor and the IDMC and described in the 
charter.  
4.1.2.
INTERIM ANALYSIS TO ASSESS BENEFIT RISK 
The interim analysis outputs will be prepared by IQVIA Biostatistics in accordance with the SAP and the IDMC 
charter. Per the Protocol, the data cut-off (DCO) for the interim analysis is to occur approximately 9 months after 
the start of treatment for the 75th subject treated in the Phase 2 part of the study.   
The interim efficacy analysis will focus on response rate and duration of response (as per ICR) as well as available 
PFS and OS data. In addition, safety data will also be reviewed to allow an overall assessment of benefit risk.   
Depending on the strength of the data, there may be an opportunity to engage with the regulatory authorities 
with a view to submit this interim data for marketing approval. As a result, the interim analysis data will also be 
shared with Immunocore’s Head of Research and Development. Further details are provided in the IDMC charter.  
  


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 20 of 131
5.ANALYSIS SETS 
Agreement and authorization of patients included/excluded from each analysis set will be conducted prior to the 
Interim, Primary and Final analysis of the study.  
All patients are considered for each of the below analysis sets, including those in the Phase 1 dose escalation and 
Phase 2 Expansion cohort parts of the study. 
5.1.
ALL PATIENTS ENROLLED SET   
The All Patients Enrolled (ENR) set will contain all patients who provide the main informed consent for this study. 
Patients who sign pre-screening informed consent but not the main informed consent will not appear in this 
analysis set. The All Patients Enrolled Set will be used to summarise patient disposition and the analysis sets.  
Any subjects who signed the main informed consent, but never started the study treatment for any reason will be 
regarded as screen failures. For these patients, the eCRF data collected will not be included in summary analyses 
but will be reported in the CSR as part of the listings for patient disposition, treatment allocation and 
inclusion/exclusion criteria.  
5.2.
FULL ANALYSIS SET  
The Full Analysis Set (FAS) comprises all patients assigned to treatment, who received at least one full or partial 
dose of IMCgp100. The FAS will be used for all demography, baseline characteristics, 
 and efficacy data 
summaries and analyses unless specified otherwise. Patients will be analyzed according to the planned treatment. 
5.3.
PER-PROTOCOL SET  
The Per-Protocol Set (PPS) consists of a subset of FAS patients in the Phase 2 part of the study who meet these 4 
criteria: (1) presence of measurable disease at baseline according to Investigator assessment based on RECIST v1.1, 
(2) >1 post-baseline tumor assessment or discontinue prior to the first tumor assessment, (3) received at least one 
full or partial dose of treatment and, (4) no violation of key inclusion or exclusion criteria (as defined below). 
Patients who are enrolled in violation of these key inclusion or exclusion criteria will be considered as major 
Protocol violations and will not be included in the PPS. 
For the (4) components above, only key inclusion criteria will be considered and will be determined based on values 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 21 of 131
entered on the Inclusion/Exclusion Criteria eCRF page. The key inclusion criteria considered as major protocol 
violations are #3, #6, and #9 as presented in the table below: 
Protocol version number 
Inclusion criteria number 
Inclusion text 
1 - 8 
03 
Histologically 
or 
cytologically 
confirmed diagnosis of mUM 
1 - 4 
06 
HLA-A2 positive 
5 - 8 
06 
HLA-A*0201 positive by central 
assay 
8 
09 
Prior therapy requirements as 
defined in Phase 2 Cohort A or B. 
 
Patients in the PPS will be classified according to planned treatment. The PPS will define the patients used in both 
the sensitivity analysis of the Primary Efficacy endpoint (i.e. ORR) and one of the Secondary Efficacy endpoints 
(DOR) for the Phase 2 expansion cohort only. If the PPS and the FAS are identical, then analyses described for the 
PPS below will not be performed. 
5.4.
SAFETY SET  
The Safety Set (SAF) includes all patients who have received at least one full or partial dose of IMCgp100. Patients 
will be classified in this set according the actual dose cohort (or the single Expansion cohort in Phase 2) they were 
assigned to, unless there is evidence from the Protocol Deviations log or the dosing data that an incorrect 
treatment was received. For example, if a patient received the dose of another cohort (different to their assigned 
dose cohort) then they will be assigned to the cohort corresponding to the dose they received. Note that a dose 
reduction is not considered an incorrect treatment. 
The safety set will be used for the safety, immunogenicity and pharmacokinetic summary of the study. 


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PROTOCOL IMCgp100-102 
Page 22 of 131
6.GENERAL CONSIDERATIONS 
6.1.
REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/stop day of assessments 
and events. 
Reference start date is defined as the day of the first dose of study drug, (Day 1 is the day of the first dose of study 
drug).  
x
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1. 
x
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, and 
Study Day and any corresponding durations will appear as missing in the listings. 
6.2.
BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement (including unscheduled 
assessments) taken prior to the first dose of treatment received (e.g. C1D1 pre-dose). In the case where the last 
non-missing measurement and the reference start date and time coincide, that measurement will be considered 
pre-dose and included in the baseline calculation as appropriate. This will be the rule for demography, other 
baseline characteristics (including disease status), efficacy tumor assessments, laboratory data, ECG data, vital 
signs data, physical examination data, ADA data, and PK data. The exceptions to this rule are adverse events (AEs) 
and concomitant medications (CMs) commencing on the reference start date, which will be considered post-
baseline. If any ECGs or vital signs are recorded in the “pre-dose panel” on C1D1 but appear with a time after the 
time of first dose, then they will be queried, but they will be assumed to be ‘post-dose’ (and therefore excluded 
from the baseline calculation), unless corrected otherwise. 


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6.3.
RETESTS, UNSCHEDULED VISITS AND END OF TREATMENT DATA 
In general, for by-visit summaries, data recorded at the nominal or observed visit will be presented. Unscheduled 
measurements will not be included in by-visit summaries, but will contribute to the baseline value, or best/worst 
case value where required (e.g. shift tables).  
In the case of a retest (same visit number assigned), the earliest available measurement for that visit will be used 
for by-visit summaries. For best/worst case (e.g. shift tables), all available measurements including retest values 
will be used. 
End of Treatment (EOT) visits will be summarized together in the by-visit summaries. 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
6.4.
WINDOWING CONVENTIONS  
There will be no post-hoc visit windowing for the analyses performed for this study. All data will be organized and 
analyzed according to the scheduled visit times (allowing for ± 7 days) as outlined in the Protocol and by the visit 
denoted on the eCRF.  
Any unscheduled visits will be organized according to the closest scheduled visit they occurred to, using the 
previous scheduled visit as part of the unscheduled visit label.  
6.5.
STATISTICAL TESTS 
There will be no formal statistical testing of data. Where appropriate, confidence intervals (CIs) will be presented. 
6.6.
COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 
x
Test Value at Visit X – Baseline Value 


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6.7.
SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 in a Windows operating system.  
7.STATISTICAL CONSIDERATIONS 
Data will be presented by dose cohort and total for Phase 1, with the exception of efficacy data which will be 
presented for total Phase 1 only as detailed in APPENDIX 1 - Presentation of Treatment Groups. This data can be 
shared with the full protocol team prior to primary and final analysis since the initial data from these Phase 1 
patients have already been published. 
All available data from Phase 1 and 2 at the time of the Phase 2 reporting will be included in the Clinical Study 
Report (CSR). Note this could be based on the interim or the primary analysis depending on which data cut is 
considered for the main study reporting.  
 
7.1.
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN 
ANALYSES 
Not applicable. 
7.2.
MULTICENTER STUDIES 
A summary of the number of patients per country and the number at each site within a country will be produced 
as a baseline summary. Outcome data by country or site will not be provided unless requested by regulatory or 
health authorities. 
7.3.
MISSING DATA 
Missing data in general will not be imputed.  
Missing efficacy data will be handled as described in Section 14.1.4, 14.2.2 and 14.3.2 of this analysis plan. 


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7.4.
MULTIPLE COMPARISONS/ MULTIPLICITY 
Not applicable. 
7.5.
EXAMINATION OF SUBGROUPS 
Subgroup analyses will be conducted as described in the Efficacy analyses – see Section 14.2.3.10. 
The following subgroups of interest will be explored: 
x
Age (<65 vs. ≥65) 
x
Gender (Male vs. Female) 
x
Race (White vs. Non-white) 
x
Region (North America vs. Europe) 
x
Baseline Eastern Cooperative Oncology Group (ECOG) performance status (0=Fully active vs. 1=Restricted 
in physically strenuous activity, or greater) 
x
Baseline Lactate Dehydrogenase (LDH) (≤ ULN vs. > ULN) 
x
Baseline Absolute Lymphocyte Count (ALC) (“<1.0 x 109/L” vs. “≥1.0 x 109/L”) 
x
Baseline Alkaline Phosphatase (ALP) (≤ ULN vs. > ULN) 
x
Largest liver metastasis (liver metastasis diameter < 3 cm vs. liver metastasis diameter ≥ 3 cm vs. no liver 
metastases)  
x
Prior immunotherapy (Yes vs. No) 
x
Prior therapy defined as 
o
Combination systemic therapy and any LDT 
o
Systemic therapy only 
o
LDT only 
In addition, patients with 1 line of checkpoint inhibitor and any LDT may also be explored as a subgroup  
x
Best response to prior therapy (complete response/partial response vs. stable disease vs. progressive 
disease/not evaluable/not applicable/missing) 


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Page 26 of 131
x
Best response to prior Immuno-Oncology (IO) (checkpoint inhibitors only), defined as 
o
Refractory to prior checkpoint inhibitors (i.e. Best response to any prior checkpoint inhibitor is 
progressive disease/not evaluable/not applicable/missing) 
o
Relapsed following prior checkpoint inhibitors (i.e. Best response to any prior checkpoint 
inhibitor is stable disease, partial response, or complete response) 
o
No prior checkpoint inhibitor 
x
Onset of Rash within first week of dose, defined as 
o
Rash within 7 days of first dose (between study day 1 to 7 inclusive) vs. no rash within 7 days of 
first dose 
o
Note: Rash will be identified using a medically-approved list of preferred terms provided by the 
Sponsor.  See APPENDIX 6 for details 
Subgroup categories may be combined if the number of patients within a category is not thought to be sufficient 
to analyze the efficacy.  
 
8.OUTPUT PRESENTATIONS 
APPENDIX 1 shows conventions for presentation of data in outputs.  
The template shells provided with this SAP describe the presentations for this study and therefore the format and 
content of the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
9.DISPOSITION AND WITHDRAWALS 
All patients who provide main informed consent will be accounted for in this study.  
Patient disposition and discontinuation/withdrawals, and inclusion and exclusion criteria will be presented for the 
ENR. All Protocol deviations will be reviewed by the medical monitor and other team members as appropriate 
before the primary and final analysis, and those deviations identified as Important (including those defined in 
Section 5.3) will be summarized and listed for the FAS. 


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10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the FAS. 
The following demographic and other baseline characteristics will be summarized and listed for this study: 
1. Demography 
x
Age (years) – continuous 
x
Age groups (years) 
o
< 65 
o
≥ 65 
x
Sex 
x
Is the patient of child bearing potential? (females only) – listed only 
x
Race 
x
Ethnicity  
x
Country 
x
ECOG performance status at Baseline 
x
Baseline LDH 
o
≤ULN 
o
>ULN 
x
Baseline ALP 
o
≤ULN 
o
>ULN 


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x
Baseline ALC 
o
<1.0 x 109/L 
o
≥1.0 x 109/L 
x
Smoking history/status including pack years 
x
Weight (kg) 
x
Height (cm) 
x
BMI (kg/m2) 
2. Disease data 
x
Diagnosis and extent of cancer (disease at Baseline). 
x
Presence of liver metastases (largest liver metastasis diameter <3 cm vs. largest liver metastasis 
diameter ≥3 cm vs. no liver metastases).  
x
Prior anti-cancer therapy, including (a) the number (%) of patients within the prior therapy categories 
and prior immunotherapy types in Section 7.5 above and including checkpoint inhibitor class PD-
1/PD-L1 and CTLA4 and other immunotherapies, (b) medically-reviewed categories of Therapy Class. 
x
Best response on prior anti-cancer therapy for metastatic disease (as identified by medical review) as 
the number and % of patients with complete response, partial response, stable disease, progressive 
disease or not evaluable or missing as per Investigator recorded assessment, based on the subset of 
the FAS who have prior anti-cancer therapy for metastatic disease data recorded. The best response 
may be repeated on further categories and sub-categories of prior anti-cancer therapies (as identified 
by medical review). 
Pregnancy test results for women of child bearing potential will be collected at Screening and over the course of 
the study. This information will be presented in a data listing only. 
 
 


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10.1.
DERIVATIONS 
x
Age (years) will be derived using the following SAS code:  
floor ((intck(‘month’,&birth,&date) - (day(&date) < day(&birth))) / 12) 
o
&birth = Date of birth 
o
&date = Date of informed consent 
o
Note: For countries where only the year of birth is provided due to privacy laws, impute birth 
month and day as June 15. This will only be done as necessary and in analysis derived datasets, 
not in SDTM (Study Data Tabulation Model) datasets. 
x
Time since primary diagnosis (years) = (Date of treatment start date – Date of primary diagnosis + 1) 
/ 365.25 
x
Time since first metastases (years) = (Date of treatment start date – Date of first metastasis + 1) / 
365.25 
x
Time from primary diagnosis to metastatic disease (years) = (Date of metastatic disease – Date of 
primary diagnosis + 1) / 365.25 
o
Note: Partial primary diagnosis dates are imputed using 15th day of month if only month/year 
present or July 02 if only year present. 
x
Best response on any prior anti-cancer therapy for metastatic disease = the “best” best response as 
derived from the Prior Anti-Cancer Therapy (PAT) eCRF page, considering all medications identified 
from the medical review. From best to worst, the following order will be used:  
o
Complete Response 
o
Partial Response 
o
Stable Disease 
o
Progressive Disease 


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o
Non-Evaluable 
o
Not Applicable 
x
BMI (kg/m2) = weight (kg) / (height (cm) / 100)2 
Note that the date of informed consent will be the main date of informed consent, not the date of pre-screening 
informed consent and not the date of informed consent for continuing treatment post RECIST-PD. 
11. SURGICAL AND MEDICAL HISTORY 
Medical History information will be listed only.  
x
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) central 
coding dictionary, using version 22.0 or later (i.e. a later version of MedDRA may be available and 
used at the time of coding for the reporting period). 
x
Medical History conditions are defined as those conditions beginning prior to screening which stop 
prior to/are ongoing at Screening.  
x
Presented by System Organ Class (SOC) and Preferred Term (PT).  
12. CONCOMITANT MEDICATIONS 
Concomitant medications and significant non-drug therapies as recorded on the Prior and Concomitant 
Medications eCRF page will be presented and coded using the World Health Organization drug dictionary (WHODD) 
Anatomical Therapeutic Chemical (ATC) classification system, dated March 2019 or later (i.e. a later version of 
WHODD may be available and used at the time of coding for the reporting period).  
Medications will be listed and summarized with the number and percent of patients receiving concomitant 
medications by ATC level 2 (coded) and Preferred Name (coded). Concomitant Intravenous (IV) fluids will be 
summarized by ATC level 3 coded term ‘I.V. SOLUTION ADDITIVES’ and Preferred Name (coded). 
The number and percent of patients receiving concomitant anti-cancer therapy regimens will be also be 
summarized, as noted in Section 12.1 below. All prior anti-cancer therapies are collected at Screening and are 
described above in Section 10. Anti-neoplastic therapies since discontinuation of study treatment are described in 
Section 12.2 below. 


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See APPENDIX 2 for handling of partial dates for medications from the Prior and Concomitant Medications eCRF 
page. In the case where it is not possible to define a medication as prior, concomitant, or post treatment, the 
medication will be classified by the worst case; i.e. concomitant.  
x
‘Prior’ medications are medications which started and stopped prior to the first dose of study drug.  
x
‘Concomitant’ medications are medications which:  
o
started prior to, on or after the first dose of study drug and no later than the last dose of study 
drug,  
o
AND ended on or after the date of first dose of study drug or were ongoing at the end of the 
study. 
x
‘Post’ medications are medications which started after the last dose of study drug. 
12.1.
PROHIBITED CONCOMITANT MEDICATIONS/THERAPIES 
During the ‘concomitant’ period of the study (as above), patients may not receive other additional investigational 
drugs, agents, devices, chemotherapy, or any other therapies that may be active against cancer. While systemic 
corticosteroid therapy will interfere with the mechanism of action of the study drugs, its use is recommended in 
some settings. See Protocol Section 6.5.3 for further details. 
Medications/therapies that are prohibited during the study will be flagged in the listing of concomitant 
medications, as well as summarized in a table by Preferred Name. These will be identified using a medically-
approved list of Preferred Names provided by the Sponsor. See APPENDIX 2 for handling of partial dates for 
concomitant alternative cancer therapies under Algorithm for Prior / Concomitant Medications. 
12.2.
ANTI-NEOPLASTIC THERAPIES POST TREATMENT 
Anti-neoplastic therapies since discontinuation of study treatment will be collected during the 90-day Safety 
follow-up, Disease Progression follow-up and Survival follow-up periods of the study. The information for those 
patients having these therapies is recorded on the Antineoplastic therapies since discontinuation eCRF page, 
separately from any ‘prior’ or ‘concomitant’ anti-cancer therapies.  
It will be assumed that data collected on the Antineoplastic therapies since discontinuation eCRF page are ‘post’ 
medications, unless a Start Date entered is ≤ the date of last dose of study drug. In this case, the Start Date will be 


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queried, but it will be assumed that the therapy was ‘concomitant’, unless corrected otherwise. See APPENDIX 2 
under Algorithm for Anti-Neoplastic Therapies Post Treatment Discontinuation for handling of partial dates for 
therapies from the Antineoplastic therapies since discontinuation eCRF page. If this imputation of a Start Date 
yields a date after the Stop Date, then impute the Start Date to be equal to the Stop Date instead. 
Anti-neoplastic therapies post treatment will be presented in a data listing and summarized as follows: 
The number and % of patients receiving subsequent therapy will also be summarized as well as the actual therapy 
received. Included in the summary will be medically-reviewed categories of Therapy Class. 
Further summaries for anti-neoplastic therapies post treatment are described in Section 18.3.  
13. STUDY DRUG EXPOSURE 
Total actual dose received, duration of treatment in days, dose intensity, and relative dose intensity will be 
summarized for IMCgp100. Also, number of cycles will be presented in the summary.  
Tolerability of study drug will be assessed by summarizing the number and duration of treatment dose 
interruptions, and the number of treatment dose reductions for IMCgp100. Reasons for dose interruptions and 
reasons for dose reductions will also be summarized, as well as listed.  
The SAF analysis set will be used for presenting all exposure and tolerability variables. 
13.1.
STUDY DRUG EXPOSURE DERIVATIONS 
A cycle is defined as 28 days = 4 weeks, and there is 1 dose administration visit every week.  
The following will be derived: 
x
Number of cycles started = total number of cycles of study drug received (including partial cycles and 
reduced doses). 
x
Number of cycles completed = total number of complete cycles of study drug received without any 
interruption (but including reduced doses). 
x
Total planned dose = sum of the total dose levels that a patient planned to receive during the study, up 
to the date of last study drug administration.  
x
Duration of treatment (days) = (date of last study drug administration – date of first study drug 
administration + 1). Note that this calculation does not include any post dose rest period.  
x
Duration of interruption (days) = (start date of next study drug administration following interruption - date 


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of visit in which interruption started). Note that this is calculated for each interruption a given patient has 
and is only calculated where study drug administration restarts following interruption.  
o
“Date of visit in which interruption started” = ‘date of visit’ from the Date of Visit eCRF pages, 
where the visit may also be a visit classified as “not done”. If it is clear that an interruption to 
dosing has occurred, but no Date of Visit eCRF page nor Administration of Study Drug eCRF page 
is entered at least 14 days (i.e. at least 7 days ± 7 day visit window) following the previous dosing 
visit, where dosing would have been expected, then the date of the expected next dose following 
last administered dose, may be used instead (=previous ‘start date of study drug administration’ 
+ 14 days). For these cases where 14 days are added, a dose interruption can be counted where 
there is a gap from a given ‘start date of study drug administration’ ≥ 15 days from the previous 
populated ‘start date of study drug administration’, between two consecutive dosing visits. See 
the definition of a dose interruption below. 
o
If a patient does not have a “start date of next study drug administration following interruption” 
then a dose interruption is not counted because either: 

The Date of study drug discontinuation from the End of Treatment page of the eCRF is 
filled out, in which case the study drug was discontinued rather than interrupted, or  

The outcome (interruption or discontinued) is unknown at the time of data cut-off, 
where the study drug discontinuation from the End of Treatment page is missing and 
study drug administration remains skipped or omitted. In this case, it is assumed there 
was no interruption, until there is evidence of the study drug administration restarting. 
x
Total actual dose received = sum of the total dose (in mcg) that a patient received during the study, up to 
and including date of last study drug administration.  
x
Dose intensity (dose per week) = [Total actual dose received / (Duration of treatment (days) + 6)] × 7, 
where adding 6 additional days to the duration accounts for the weekly dose administration. 
x
Planned dose intensity (dose per week) = [Total planned dose / (Duration of treatment (days) + 6)] × 7, 
where adding 6 additional days to the duration accounts for the weekly dose administration. 
x
Relative dose intensity (%) = (Dose intensity / Planned dose intensity) × 100. 
Additional Notes on Derivations: 
a. The Administration of Study Drug eCRF page will be used for these calculations. 
b. The number of cycles started is counted for all cycles of dosing in which study drug was actually 
administered. Any administration of study drug received, regardless of the ‘Actual dose administered’ on 
the eCRF (any dose > 0 units), that occurs in a given cycle (as indicated by the visit) will be counted as one 
cycle of that study drug. 


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i.
Note: Multiple doses within a Cycle do not count multiple times towards the number of cycles 
started. For example, four doses (> 0 units) of IMCgp100 during visits in Cycle 1 count as one 
cycle of study drug since all these dose administrations occurred during a single Cycle (i.e. Cycle 
1).  
c.
The number of cycles completed is counted for all cycles of dosing in which study drug was actually 
administered, and furthermore where no interruption occurs. Therefore, in a 4-week cycle, all doses each 
week must be administered for the entirety of the cycle, in order to count. Reduced doses are allowed, 
as per number of cycles started above. 
d. The total planned dose is based on the dose level a patient is originally assigned to, noting that subjects 
are planned to receive 20 mcg IMCgp100 at C1D1 and 30 mcg IMCgp100 at C1D8. Intra-subject dose 
escalation occurs at C1D15, with dose level set depending on cohort and all dose administrations from 
this day are expected to be at that dose level. For Phase 1 and 2 patients enrolled to the study and 
assigned to treatment under Protocol Amendment 5 and earlier, the Dose Re-Mapping Table below 
applies, in which the Corrected Dose levels are used instead. The planned dose level is used over all visits 
where a patient planned to receive study drug, even if the dose is missed during the visit, up until the cut-
off as described above. This calculation is necessary for the planned dose intensity, which is used to 
calculate the relative dose intensity. 
i.
Any scheduled CxDy visits with ‘date of visit’ from the Date of Visit eCRF page ≤ date of last study 
drug administration are included in the calculation, by adding the appropriate planned dose level 
for the given visit.  If a patient has not yet discontinued treatment on the End of Treatment page, 
then all applicable scheduled CxDy visits through the date of last recorded study drug 
administration are considered, up until the data cut-off. 
ii.
Example: In Phase 2, patients are planned to receive 20 mcg at C1D1, 30 mcg at C1D8, and then 
68 mcg from C1D15 onwards. Therefore, the total planned dose is calculated as the sum of 20 
mcg + 30 mcg + 68 mcg at C1D15 onwards, over all visits where a patient planned to receive 
study drug.  
e. The total actual dose received is based on the ‘Actual dose administered’ entered on the eCRF for each 
visit administration of study drug. The actual dose administered is summed up over all visits where a 
patient actually received study drug, up to and including the day of last study drug administration. For 
Phase 1 and 2 patients enrolled to the study and assigned to treatment under Protocol Amendment 5 and 
earlier, the Dose Re-Mapping Table below applies, in which the Corrected Dose levels are used instead 
of the values entered on the eCRF. 
f.
The date of first study drug administration is taken from the earliest ‘Dose start date’ entered on the 
eCRF. 
g.
The date of last study drug administration is taken from the latest ‘Dose end date’ entered on the eCRF. 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 35 of 131
Dose Re-Mapping Table: 
Protocol Amendment 5 and 
earlier dose levels (as entered 
on eCRF) 
Corrected Dose, planned and 
received on or prior to April 7, 
2017 
Corrected Dose, planned and received 
after April 10, 2017 
20 mcg 
No update to dose 
No update to dose 
30 mcg 
No update to dose 
No update to dose 
50 mcg 
No update to dose 
No update to dose 
60 mcg 
54 mcg 
54 mcg 
70 mcg 
67 mcg 
64 mcg 
80 mcg 
76 mcg 
73 mcg 
75 mcg 
68 mcg 
68 mcg 
 
Definitions of Dose Interruption/Reduction: 
x
Dose interruption – an entire planned dose dosing visit is skipped or entered as omitted in the eCRF. 
To clarify, if a dose on a single day is stopped and restarted, but a partial or full dose is still taken on 
same visit (i.e. same Visit label on the eCRF), then this is not a dose interruption. Dose interruptions 
will be flagged on the Administration of Study Drug eCRF page where the response to ‘Did the patient 
receive investigational product at this visit?’ is equal to ‘No, reason for dose omission’. Also, dose 
interruptions are counted in cases where a patient misses an entire study visit, where dosing is 
expected, as per the derivation of total planned dose above. Therefore, any CxDy visits with ‘date of 
visit’ from the Date of Visit eCRF page ≤ ‘date of discontinuation’ from the End of Treatment page are 
considered to be skipped and interrupted, if dose was not administered and study drug 
administration restarts following interruption. If there is no ‘date of discontinuation’ date, then all 
CxDy visits with a populated ‘date of visit’ are considered in the calculation. 
o
Skipped or omitted dosing visits are only counted towards a dose interruption, if study drug 
administration restarts following interruption. Therefore, as per the Duration of interruption 
definition above, a “start date of next study drug administration following interruption” 
must exist, for a dose interruption to count. 

Note: skipped or omitted dosing visits leading to discontinuation of study drug, are 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 36 of 131
counted separately in the Disposition summary under patients who discontinued 
treatment. 
o
A single interruption is defined as any length of time a patient misses dosing visits. For 
example, for IMCgp100 which is administered weekly, a single dose interruption would be 
defined regardless of whether only 1 week was missed or 2 consecutive weeks dosing were 
missed. 
o
An interruption to dosing may occur, in which no Date of Visit eCRF page nor Administration 
of Study Drug eCRF page is entered at least 14 days (i.e. at least 7 days ± 7 day visit window) 
following the previous dosing visit, where dosing would have been expected between two 
consecutive visits. In this case, a dose interruption may be counted where there is a gap 
from a given ‘start date of study drug administration’ ≥ 15 days from the previous populated 
‘start date of study drug administration’, between two consecutive dosing visits. Note: there 
must be a restart of study drug administration following interruption, for this to count. 
x
Dose reduction from protocol dose level – restarting treatment at a reduced dose of study drug. Dose 
reductions will be derived from the Administration of Study Drug eCRF page where either (i) the 
‘Actual dose administered’ is lower than the protocol specified dose level while patients are 
escalating from 20 mcg to 30 mcg to the planned/assigned dose level for each cohort, or (ii) the 
‘Actual dose administered’ at a given visit decreases from the ‘Actual dose administered’ at the 
previous dose administration visit.  
o
(i) It is conceivable that the planned starting doses of 20 or 30 mcg may continue through 
the C1D15 visit and beyond. The reasons given are highlighted in the eCRF, in the section 
‘Has the dose reduced from previous visit?’. In these cases, where the planned starting dose 
of 20 or 30 mcg continue, each repetition of a ‘Actual dose administered’ = “20 mcg” or each 
repetition of a ‘Actual dose administered’ = “30 mcg” will be considered as a dose reduction 
from protocol dose level. 
o
(ii) From C1D15 onwards, or from the first post-C1D15 visit that the escalated dose is 
expected to be received (if the planned starting doses of 20 or 30 mcg continue through 
C1D15 and beyond), dose reductions are where the ‘Actual dose administered’ at a given 
visit decreases from the ‘Actual dose administered’ at the previous dose administration visit. 
In this second aspect of the dose reduction criteria, only the initial reduction of a ‘Actual 
dose administered’ will be considered as a dose reduction from protocol dose level. 

For example, in Phase 2 where patients are planned to receive 68 mcg from C1D15 
onwards, a reduction to say 50 mcg at C1D22 from the 68 mcg at C1D15 is counted 
as a dose reduction. But continuing to be prescribed 50 mcg at C2D1 onwards is not 
considered further dose reductions. However, if the patient increases their dose 
level back up to 68 mcg at a visit, and then reduces again back down to 50 mcg, 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 37 of 131
then the initial reduction back down to 50 mcg is again counted as a dose reduction. 
Similarly, an exposure profile of: 20-30-68-50-50-30 is considered to consist of two 
dose reductions, the first reduction from 68 to 50 mcg and the second reduction 
from 50 to 30 mcg.  
o
Note: Any dose reduction from protocol dose level will be both summarized with the 
corresponding reason (Adverse Event or Other), as well as listed. 
x
Dose reduction from prescribed dose – Any case where the ‘Actual dose administered’ is lower than 
the ‘Prescribed dose level’ at a given dose administration visit. Note: The ‘Prescribed dose level’ is 
entered by the Investigator as the intended/planned dose to be received at a given visit, even if that 
is less/reduced from the Protocol-specified dose level.  
o
Unlike, the above dose reduction from protocol dose level which will be summarized, a dose 
reduction from prescribed dose will only be listed as “Planned dose?” = ‘No’. It is expected 
that the only kind of dose reductions from prescribed dose are caused by infusion 
extravasation events, also recorded on the AE/SAE eCRF page. Apart from these types of 
events, all other cases where ‘Actual dose administered’ is lower than the ‘Prescribed dose 
level’ will be queried with Data Management. 

Note: Due to an infusion extravasation event, an infusion may stop and restart, and 
then a partial or full dose may still be taken on the same visit. In the case of a full 
dose being administered after a stop/restart, a dose reduction from prescribed 
dose will not count, and in this case, the record of this occurring will be shown in 
the exposure and AE data listings. Only when less than the prescribed dose is 
administered at a visit (i.e. a partial dose) will “Planned dose?” = ‘No’. Otherwise, 
“Planned dose?” as entered on the eCRF should be ‘Yes’. 

Note: Both kinds of dose reductions, (1) a dose reduction from protocol dose level 
and (2) a dose reduction from prescribed dose, can both occur at the same visit if 
an intended reduction was planned by the investigator, and then on top of that the 
‘Actual dose administered’ is lower than the ‘Prescribed dose level’, due to an 
infusion extravasation event. 
 
Other definitions:  
x
Received intra-patient dose escalation as planned– defined as receiving the full planned cohort-specified 
dose level on C1D1 (i.e. 20 mcg IMCgp100), C1D8 (i.e. 30 mcg IMCgp100), and C1D15 (i.e. the planned/ 
IVRS assigned dose level for a particular cohort). 
 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
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Further notes on exposure: 
x
When dose is interrupted, reduced, or discontinued due to an Adverse Event (AE), then the “Action taken 
with study drug” item on the AE/SAE eCRF page should be completed accordingly. However, the Action 
can only be selected once per AE, so in the case that interruptions/reductions/discontinuation are 
consecutive on the Administration of Study Drug eCRF page, then the AE/SAE eCRF page may only have 
the most extreme and ultimate Action recorded. The order of extremity from least extreme to most 
extreme is: an interruption, a reduction, and a discontinuation. 
13.1.1. MISSING DATA METHODS FOR STUDY EXPOSURE VARIABLES 
Missing data for elements of certain study exposure variables will be handled as follows: 
x
The date of first study drug administration is not expected to be missing for any patients.  
x
If the date of last study drug administration is missing or partial, then the date will be taken instead from 
the Date of discontinuation on the End of Treatment page of the eCRF. 
x
The handling of missing start/end dates from the Administration of Study Drug eCRF page that are not the 
first/last study drug administrations are to be as follows: 
o
If the dose start date is missing and the dose end date is known, then the start date is set to the 
end date. 
o
If the study drug end date is missing and the dose start date is known, then the end date is set 
to the start date.  
o
If both dose start and end date are missing from the Administration of Study Drug eCRF page 
then these are set to a known date from a Date of Visit eCRF page. 


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STATISTICAL ANALYSIS PLAN: 
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Page 39 of 131
14. EFFICACY OUTCOMES  
14.1.
PRIMARY EFFICACY 
14.1.1. PRIMARY EFFICACY VARIABLES & DERIVATIONS 
Phase 1 dose escalation 
Not applicable, the primary endpoint is a safety endpoint.  
Phase 2 dose expansion  
For Phase 2 dose expansion, the primary efficacy variable is the objective response rate, defined as the proportion 
of patients with a best overall response of complete response (CR) or partial response (PR) based on the ICR data, 
according to RECIST v1.1. The denominator in the calculation of the ORR will be the number of patients in the FAS. 
Data summaries and listings will be presented overall for the Phase 2 expansion cohorts. 
All guidelines for the implementation of RECIST v1.1 based on ICR are given in the Independent Review Charter.   
14.1.2. DERIVATION OF BEST OVERALL RESPONSE USING RECIST V1.1 CRITERIA 
To determine whether an objective response (i.e. CR or PR) exists for a patient, the best overall response (BOR) to 
a patient’s tumor assessments during the study will be derived as follows. 
A BOR is calculated based on the overall visit responses from each RECIST assessment. It is the best response a 
patient has had following the date of first dose of study drug, but on or prior to either (i) disease progression 
according to RECIST v1.1, (ii) the last evaluable tumor assessment in the absence of disease progression (including 
death), or (iii) starting any subsequent alternative cancer therapy including another investigational agent, 
whichever comes first. In other words, for patients who progress and subsequently have a response, the BOR will 
not include the response after progression. Furthermore, tumour assessments performed after initiating another 
anti-cancer therapy will not be included in the calculation of BOR. See Sections 12.1 and 12.2 for how alternative 
cancer therapies are collected while concomitant with study drug treatment and post treatment.  
The individual visit overall responses from each RECIST assessment will be provided by ICR as part of an external 
data transfer. Using these overall responses at each visit, a patient’s BOR is derived in the following order, checking 
for best outcome before worst: 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 40 of 131
1. Complete Response (CR): At least one confirmed visit response of CR. 
2. Partial Response (PR): If not CR, at least one confirmed visit response of PR. 
3. Stable Disease (SD): If not CR/PR, at least one visit response of SD recorded at least 8 weeks after 
date of first dose of study drug. Includes unconfirmed CR or PR recorded at least 8 weeks after date 
of first dose of study drug. 
4. Progressive Disease (PD): If not CR/PR/SD, a disease progression or death in the absence of 
progression 
5. Not-Evaluable (NE): No evidence of CR, PR, SD, or PD. Either by default or the only visit response by 
ICR is ‘NE’. 
Further considerations for deriving BOR: 
x
Stable disease should be recorded at least 8 weeks ± 1 week, i.e. at least 49 days (to allow for the 
assessment window), after first dose. For determination of a best response of SD, the earliest of the dates 
contributing towards a particular overall visit assessment will be used. The same goes for determining a 
best response of SD for any unconfirmed CR or PR recorded at least 8 weeks after first dose. 
x
Patients who have a PD event (progression or death) after 2 or more consecutive missed/non-evaluable 
tumor assessment visits, will not contribute to the BOR derivation. Specifically: 
o
For patients who die with no evaluable follow-up tumor assessments or no evaluable baseline 
assessment, if the death occurs after 2 visits of the first dose of study drug, then the BOR will be 
NE.  
o For patients who die with no evaluable follow-up tumor assessments or no evaluable baseline 
assessment, if the death occurs within 2 visits of first dose of study drug, then the BOR will be 
PD (for death in the absence of progression).

Note: the definition of 2 visits (allowing for early and late visits) in this case equates to 
18 weeks (126 days) from the first dose of study drug. 
o
Note: The scheduled tumor assessment scheme for RECIST is mandated every 8 weeks (±1 week) 
from Cycle 3 Day 1 until 40 weeks on study (approximately Cycle 11 Day 1). Thereafter, tumor 
assessments are every 12 weeks (±1 week) until disease progression or patient withdrawal. 
Therefore, in order to determine if a PD event occurred after 2 missed/non-evaluable tumor 
assessment visits, the definition of 2 visits (allowing for early and late visits) will be as follows: 

If the previous evaluable tumor assessment is less than study day 218 (i.e. just prior to 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
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week 31), then 2 visits equates to 18 weeks (126 days) from the previous evaluable 
tumor assessment. 
x
Unless the previous evaluable tumor assessment is at Screening or there are 
no evaluable tumor assessments, in which case 2 visits equates to 18 weeks 
(126 days) from the date of first dose of study drug. 

If the previous evaluable tumor assessment is greater than or equal to study day 218 
and less than study day 288 (i.e. from week 31 to just prior to week 41), then 2 visits 
equates to 22 weeks (154 days) from the previous evaluable tumor assessment. This is 
because 2 missed/non-evaluable tumor assessment visits over this specific time period 
would be when the scheduled frequency of tumor assessments changes from every 8 
weeks (±1 week) to every 12 weeks (±1 week). 

If the previous evaluable tumor assessment is greater than or equal to study day 288 
(i.e. week 41 onwards), then 2 visits equates to 26 weeks (182 days) from the previous 
evaluable tumor assessment. 
o
The date of progression will be determined based on the earliest of the imaging dates of the 
component that triggered the progression. This could be a mixture of the target, non-target, 
and/or new lesion imaging dates. To determine which components (as determined by ICR) led to 
progression, the individual RECIST visit responses recorded by the ICR will be used. If the “Target 
lesions response” = PD, then the earliest target lesion imaging date will be considered. Likewise, 
if the “Non-target lesions response” = PD, then the earliest non-target lesion imaging date will 
be considered. Finally, if “New Lesions” = UNEQUIVOCAL, then the earliest new lesion imaging 
date will be considered. 
14.1.3. CONFIRMATION OF OBJECTIVE RESPONSE USING RECIST V1.1 CRITERIA 
Confirmation of response is required for declaring PR or CR in the ORR. A confirmed response is defined as an initial 
response (CR or PR) followed by a response at least 4 weeks later (for CR this needs to be confirmed by CR and for 
PR this needs to be confirmed by either PR or CR). The initial overall visit assessment which showed a response will 
use the latest of the imaging dates contributing towards a particular overall visit assessment. The same will be 
done for the confirmation overall visit assessment. 
In the case where a patient has two non-consecutive visit responses of PR, then, as long as the time between the 
2 visits of PR is greater than 4 weeks and there are no PD between the PR visits, the patient will be defined as a 
responder. For confirmation of response to count, visit responses of NE are allowed between visit responses of CR 
to confirm a CR, and likewise, visit responses of NE or SD are allowed in between visit responses of PR/CR to confirm 
a PR. For example, if a patient has visit responses of CR, NE, CR, then, as long as the time between the 2 visits of 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
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CR is greater than 4 weeks, then a best response of CR will be assigned. 
See Table 7-2 of the Protocol for the disease assessment collection plan. 
PD per RECIST v.1.1 does not require confirmation. 
14.1.4. MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE 
No adjustments for missing data will be made for the RECIST v1.1 criteria that are used for the Phase 2 primary 
efficacy analyses. However, an underlying assumption will be made such that missing tumor response data is not 
indicative of a complete or partial (objective) response. Therefore, any missing overall visit responses for RECIST 
tumor assessments are considered as Not Evaluable in the calculation of the BOR.  
14.1.5. PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLES 
Phase 1 dose escalation 
Not applicable, the primary endpoint is a safety endpoint. 
Phase 2 dose expansion 
For Phase 2 dose expansion, ORR will be estimated according to the number and % of patients with an objective 
response (BOR of CR or PR). The associated 95% two-sided confidence interval for the true ORR using the exact 
Clopper-Pearson method (Clopper & Pearson, 1934) will also be presented. 
BOR and ORR will be summarized based on the patients in the FAS.  
 
14.1.6. SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
Phase 2 dose expansion – Repeat using Per-Protocol Set 
For the primary analysis for Phase 2 dose expansion, the calculation of ORR with 95% confidence intervals as 
described in Section 14.1.5.2, will also be performed using the PPS to obtain additional information on the 
robustness of results across analysis sets. If the PPS and the FAS are identical, then these additional summaries will 
not be reported.  
 


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PROTOCOL IMCgp100-102 
Page 43 of 131
14.2.
SECONDARY EFFICACY 
For the Phase 1 dose escalation, tumor based secondary efficacy endpoints will be derived and reported based on 
Investigator assessment data.  
For the Phase 2 dose expansion, tumor-based secondary efficacy endpoints will be derived and reported based on 
the ICR data. In addition, summaries based on Investigator assessment data will be produced as supportive. 
Investigator response and ICR will be derived in the same way unless specified otherwise. ICR data will be based 
on the visit responses provided by ICR and Investigator responses will be derived based on the overall visit 
responses recorded on the eCRF. Actual imaging dates will be used when deriving time-related variables or 
assessing confirmation of response. 
All secondary efficacy outputs will be based on the FAS unless otherwise stated. Data outputs for Phase 1 and 
Phase 2 will be presented together. Phase 1 data will be combined and presented as “Phase 1 dose escalation 
cohorts - Total” unless specified otherwise. Phase 2 data will be presented by overall expansion. 
Tumor- based secondary efficacy endpoints will be based on RECIST v1.1. All guidelines for the implementation of 
RECIST v1.1 criteria are given in Appendix 1 of the Protocol.   
See APPENDIX 1 - Presentation of Treatment Groups for details on how the treatment groups will be presented. 
14.2.1. SECONDARY EFFICACY VARIABLES & DERIVATIONS 
The following secondary efficacy variables will be reported based on RECIST v1.1: 
Phase 1 dose escalation:  
o
BOR, ORR, Disease Control Rate (DCR), time to response, duration of response, best percentage 
change in tumor size, and PFS based on Investigator assessment data.  
o
Overall survival. 
Phase 2 dose expansion:  
o
BOR, DCR, time to response, duration of response, best percentage change in tumour size, and PFS 
based on ICR data. Investigator assessment data will be presented as supportive (including the ORR 
endpoint).  
o
Concordance between the ICR and Investigator assessment data for BOR. 
o
Overall survival.  
o
Rate and duration of minor responses (MinR) based on ICR and Investigator assessment. 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
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BOR and ORR using RECIST v1.1 
BOR and ORR will be derived as described above for the primary efficacy in Section 14.1.2 for the following: 
x
Phase 1 and Phase 2 using Investigator assessment data. 
x
Phase 1 and Phase 2 using Investigator assessment data excluding patients with non-measurable disease 
at baseline by Investigator assessment. 
x
Phase 1 using available ICR data – BOR listed only. 
x
Phase 2 using ICR data, excluding patients with non-measurable disease at baseline by ICR. 
Note: The BOR derivation of Not-Evaluable using Investigator assessment from the eCRF is as follows: 
x
Not-Evaluable (NE): No evidence of CR, PR, SD, or PD. Either by default or the only overall visit 
response by the Investigator is ‘Not Assessable’. 
Note: ORR determined by ICR is the primary efficacy variable for Phase 2. 
Progression Free Survival  
Progression Free Survival is defined as the time from first dose of study drug until the date of disease progression 
or death (by any cause in the absence of disease progression) regardless of whether the patient withdraws from 
assigned treatment or receives another anti-cancer therapy prior to progression. 
Time for PFS will be calculated in number of months, calculated in two steps as: 
i.
Time in days = (date of event – reference date) + 1, where reference date is first dose date of 
IMCgp100. 
ii.
Therefore, time in months = days / (365.25 / 12). In other words, 1 month = 30.4375 days. 
Rules for right-censoring are as follows: 
x
Patients who have not progressed or died at the time of analysis will be censored at the time of the 
latest tumor assessment date of their last evaluable scan (Note: evaluable means an overall visit 
response not equal to NE). 
x
If a patient progresses or dies after 2 or more missed/non-evaluable tumor assessment visits, the 
patient will be censored at the date of the latest tumor assessment of their last evaluable scan. 
x
If a patient has no evaluable follow-up tumor assessments or has no evaluable baseline assessment, 
then the patient will be censored at the date of first dose of study drug (Day 1).  


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o
Note: An exception to this rule is if the patient (with no evaluable tumor assessment 
visits or no baseline data) dies within 2 visits of first dose of study drug, then the patient 
will be counted as an event. 
In order to determine whether a death/progression is censored or an event, an exact time period is needed to 
define 2 visits being missed or consecutively non-evaluable. This is defined as per the derivation of BOR for the key 
primary Phase 2 efficacy analysis in Section 14.1.2, under “Further considerations for deriving BOR”. 
Important derivation notes for PFS Time: 
x
The PFS time will always be derived based on imaging dates, not visit dates. 
x
Imaging dates contributing towards a particular visit may be performed on different dates. The following 
rules will be applied: 
o
RECIST v1.1 (Investigator assessment data): For the investigational site assessments, date of 
progression will be determined based on the earliest of the imaging dates of the component(s) 
that triggered the progression. This could be a mixture of the target, non-target, and/or new 
lesion imaging dates. To determine which components (as determined by the Investigator) led to 
progression, the individual RECIST visit responses recorded on the Assessment of disease based 
on imaging (According to RECIST 1.1) eCRF page will be used. If the “Target lesions response” = 
Progressive Disease (PD), then the target lesion imaging dates will be considered. Likewise, if the 
“Non-target lesions response” = Progressive Disease (PD), then the non-target lesion imaging 
dates will be considered. Finally, if “New Lesions” = Yes, then the new lesion imaging dates will be 
considered. 
 
o
RECIST v1.1 (ICR data): The same approach as per the Primary Analysis for Phase 2 will be used for 
ICR data, for deriving the date of progression, as per Section 14.1.2 under Further considerations 
for deriving BOR. 
 
o When censoring a patient for PFS the patient will be censored at the latest of the dates 
contributing to a particular overall visit assessment.
Overall Survival  
Overall Survival is defined as the time from the date of first dose of study drug until death due to any cause in 
general. Any patient not known to have died at the time of analysis will be right-censored based on the last 
recorded date on which the patient was known to be alive, i.e. the latest of (i) the “Date of Last Contact” (for those 
patients still alive) on the End of Study eCRF page and (ii) “Date patient last known to be alive” on the Survival 
Follow Up eCRF page. Also, to make sure that the last date patient was known to be alive is accurate as possible, 
any date from the eCRF that indicates the patient is still alive will also be considered. The eCRF pages to be included 
in this check are: AE/SAE (including hospitalization dates), Prior and Concomitant Medication, any page relating to 


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patient Disposition, Administration of Study Drug 1-3, Vital Signs, Electrocardiogram, all Laboratory pages, Physical 
Examination, Punch Skin Biopsy, all Tumor Scan pages, and ECOG Performance Status. The eCRF page dates that 
are not included in this check are: visit dates or signature dates or any other module that is not a true assessment 
date, e.g., sample processing dates. 
Time will be calculated in number of months, calculated in exactly the same way as described for PFS above. 
Duration of Response 
Duration of response is defined as the time from the date of first documented objective response (CR or PR) until 
the date of documented disease progression or death by any cause in the absence of disease progression; the end 
of response should coincide with the date of progression or death for the PFS endpoint. The time of the initial 
response will be defined as the latest of the dates contributing towards the first documented OR (i.e. partial or 
complete response). As for the ORR, an objective response here requires confirmation at least 4 weeks later. The 
initial overall visit assessment which showed a response is used for the initial response (i.e. as date of onset of 
response), as opposed to the confirmation visit assessment. 
Time will be calculated in number of months, calculated exactly the same way as described for PFS above. Time to 
response will not be defined (i.e. set to missing) for those patients who do not have documented OR. 
If a patient does not progress following a response, then their duration of response will be right-censored at the 
PFS censoring time. Duration of response will not be defined (i.e. set to missing) for those patients who do not 
have a documented OR. 
Time to Response 
Time to response is defined as the time from the date of first dose of study drug until the date of first documented 
objective response. The time of the initial response will be defined as the latest date contributing towards the first 
documented OR (i.e. partial or complete response). As for the ORR, an objective response here requires 
confirmation at least 4 weeks later.  The initial overall visit assessment which showed a response is used for the 
initial response, as opposed to the confirmation visit assessment. 
Time will be calculated in number of months, calculated exactly the same way as PFS above. Time to response will 
not be defined (i.e. set to missing) for those patients who do not have documented OR. 
Best Percent Change in Baseline of Tumor Size  
Tumor size will be defined at each visit, as entered by the investigator on the Sum of Diameters (According to 
RECIST1.1/irRC) eCRF page or as provided by ICR. 
The change from baseline in tumor size will be calculated as the difference between the tumor size at each post-


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baseline visit and the tumor size at baseline for each patient. The percent change from baseline is then calculated 
as: 
ܶݑ݉݋ݎݏ݅ݖ݁ܽݐܸ݅ݏ݅ݐܺെܶݑ݉݋ݎݏ݅ݖ݁ܽݐܤܽݏ݈݁݅݊݁
ܶݑ݉݋ݎݏ݅ݖ݁ܽݐܤܽݏ݈݁݅݊݁
ൈͳͲͲ 
The best percent change for a patient is then defined as the maximum percent reduction from baseline or the 
minimum percent increase from baseline (in the absence of a reduction) on or prior to either (i) disease 
progression, (ii) the last evaluable tumor assessment in the absence of disease progression (including death), or 
(iii) starting any subsequent alternative cancer therapy including another investigational agent, whichever comes 
first. This means the best percent change in tumor size will align with the BOR definition, as described in Section  
14.1.2 above.  
Disease Control Rate 
Disease Control Rate is defined as the proportion of patients with either an objective response (i.e. partial or 
complete response), or with a BOR of stable disease recorded at least 24 weeks (±1 week) after date of first dose 
of study drug. The estimated DCR will also be repeated using a definition of BOR of stable disease recorded at least 
16 weeks (±1 week) after date of first dose of study drug. 
Stable disease should be recorded at least 24 weeks ± 1 week, i.e. at least 161 days (to allow for the assessment 
window), after first dose. For the repeat analysis including stable disease of at least 16 weeks ± 1 week, the number 
of days used as a cut-off will be at least 105 days after first dose. The BOR of stable disease includes unconfirmed 
CR or PR in this timeframe. For determination of a BOR of stable disease, the earliest of the dates contributing 
towards a particular overall visit assessment will be used. As for the ORR, an objective response of partial or 
complete response here requires confirmation at least 4 weeks later. Stable disease does not require confirmation. 
Rate and Duration of Minor Response 
Minor response is defined as a reduction from baseline in sum of diameters between 10%–29%, where the non-
target lesion visit response is not unequivocal progression and no new lesions are present. The sum of diameters 
is defined as per RECIST v1.1 as the sum of longest diameters or short axis of target lesions (mm). Minor response 
requires confirmation at least 4 weeks after the initial response as described in Section 14.1.3 for CR and PR.  
The rate of minor response (or better) is defined as the proportion of patients with a confirmed CR, PR, or MinR. 
It will be calculated for both the Investigator assessment and ICR data following RECIST v1.1. The denominator in 
the calculation of the Minor response rate will be the number of patients in the FAS according to ICR.  
Duration of response, including minor response, will be derived as described above in Section 14.2.1.4 based on 
patients with a BOR of CR, PR, or MinR.  
Rate and duration of minor response will be defined for Phase 2 dose expansion only. 


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14.2.2. MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLES 
No adjustments for missing data will be made for any response data used for the Secondary efficacy analyses. 
However, as per the Phase 2 primary efficacy analysis, an underlying assumption will be made such that missing 
tumor response data is not indicative of a complete or partial (objective) response, nor of stable disease or 
progressive disease. Therefore, any missing overall visit responses for tumor assessments are either considered as 
Not Evaluable in the calculation of the BOR or are ignored in any of the other calculations. 
14.2.3. ANALYSIS OF SECONDARY EFFICACY VARIABLES 
BOR and ORR using RECIST v1.1 
The primary efficacy analysis of the ORR using RECIST v1.1 criteria will be repeated using the Investigator 
assessment data and ICR for Phase 1, and the Investigator assessment data for Phase 2, as described in Section 
14.1.5.2. 
The BOR, ORR and corresponding 95% confidence interval for the true ORR (using the exact Clopper-Pearson 
method (Clopper & Pearson, 1934)) will be presented based on the patients in the FAS. In addition, BOR will also 
be summarized based on the FAS to include patients only with measurable disease at baseline.  
Concordance between Investigator assessment and ICR of BOR for RECIST v1.1 
The agreement/disagreement between the Investigator assessment and ICR of BOR for RECIST v1.1 will be 
summarized for Phase 2 dose expansion.  A “shift” type summary will be presented for the frequency of BOR values 
between Investigator and ICR, for all five categories of CR, PR, SD ≥ 8 weeks, PD, and NE. Percentages will be 
displayed based on the FAS. 
Progression Free Survival 
Progression Free Survival will be presented graphically using Kaplan-Meier plots. The estimated progression free 
survival rates at 3, 6, 9 and 12 months will be estimated via the Kaplan-Meier method and displayed and repeated 
for every 3 months after if follow-up goes beyond 12 months. The corresponding 95% confidence interval (using 
the Greenwood formula method of Kalbfleisch and Prentice, 1980) for each estimated PFS rate will be presented. 
Also, median PFS time and the corresponding 95% CI (using the method of Brookmeyer and Crowley, 1982 with 
the log-log transformation) will be summarized. The number and % of patients who have had progression events 
(disease progression or death) will also be presented.  
The median follow-up time for PFS and the corresponding 95% confidence interval (using the method of 
Brookmeyer and Crowley, 1982 with the log-log transformation) will also be summarized using the reverse Kaplan-


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Meier (KM) method. The analysis involves the event and censoring rules specified in Section 14.2.1.2 to be switched 
(i.e. the patients with documented disease progression or death become ‘censored’, and the censored patients 
are treated as the ‘event’).  
Overall Survival  
Overall Survival will be graphically analyzed and summarized in the same way as PFS (see Section 14.2.3.3).  
The median follow-up time for overall survival will also be summarized using the reverse KM method in the same 
way as PFS (see Section 14.2.3.3). The analysis involves the event and censoring rules specified in Section 14.2.1.3 
to be switched (i.e. the patients with documented death become ‘censored’, and the censored patients are treated 
as the ‘event’).  
Duration of Response 
Duration of response will be graphically analyzed and summarized in the same way as PFS (see Section 14.2.3.3). 
Duration of response will be derived for patients with CR and PR only. 
The median follow-up time for duration of response will also be summarized using the reverse KM method in the 
same way as PFS (see Section 14.2.3.3). The analysis involves the event and censoring rules specified in Section 
14.2.1.414.2.1.3 to be switched (i.e. the patients with documented disease progression or death become 
‘censored’, and the censored patients are treated as the ‘event’). 
For the Phase 2 Expansion, duration of response by ICR will be reported based on the FAS. Also, this will be 
repeated for the PPS. For Phase 1, duration of response will be reported by Investigator assessment in the FAS 
only. 
Time to Response 
Time to response data will be summarized using descriptive statistics for patients with CR or PR only.  
Change in Tumor Size 
Tumor size will be presented graphically using a waterfall plot, to present each patient’s best percent change in 
tumor size as a separate bar, with the bars ordered from the largest increase to the largest decrease. For each 
patient’s bar, the best overall response will be shown using a different color for each tumor response option. 
In addition, a spider plot will be produced to display the percent change in tumor size across time for patients with 
minor response or better. 
For both waterfall and spider plots, any post-baseline visits where the number of assessable target lesions is less 
than the number of assessable target lesions at baseline, will consequently not contribute to patients’ tumor size 


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calculations to be plotted. 
Change in tumor size will be based on the FAS with measurable disease at baseline. 
Disease Control Rate  
The DCR will be summarized as described above for ORR (Section 14.2.3.1) based on the FAS.  
Rate and Duration of Minor Response  
Response rate and duration of response including minor response (i.e. for confirmed CR, PR, or MinR) will be 
summarized as described above for ORR (Section 14.2.3.1) based on the FAS, and for Phase 2 dose expansion only. 
Duration of minor response will be graphically analyzed and summarized in the same way as PFS (see Section 
14.2.3.3). Duration of response will be derived for patients with CR, PR and MinR only. 
The median follow-up time for duration of minor response will also be summarized using the reverse KM method 
in the same way as PFS (see Section 14.2.3.3). The analysis involves the event and censoring rules specified in 
Section 14.2.1.8 to be switched (i.e. the patients with documented disease progression or death become 
‘censored’, and the censored patients are treated as the ‘event’). 

Subgroup Analyses of Efficacy Variables 
Subgroup analyses will be produced as per the subgroups specified in Section 7.5 for Phase 2. The subgroup 
analyses will be produced for RECIST v1.1 by ICR for ORR, PFS, OS, and Duration of response.  
The point estimates (ORR proportion, PFS median, OS median, Duration of response median) and their 
corresponding 95% confidence intervals will also be displayed in a forest plot. The reference line on the forest plot 
will correspond to the point estimate for all patients in the FAS. 

Swimmer Plot of Tumor Data 
Swimmer plots will be produced showing duration of treatment, best overall responses (CR, PR, SD, Minor 
response, and PD according to RECIST v1.1 by ICR and/or Investigator assessment) and time to progression and/or 
death, where applicable.  


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14.3.
EXPLORATORY EFFICACY 
14.3.1. EXPLORATORY EFFICACY VARIABLES & DERIVATIONS 
The following exploratory efficacy variables will be reported: 
 
Phase 1 dose escalation: 
x
Duration of treatment post RECIST-PD based on irRECIST by ICR and Investigator  
x
BOR from start of treatment based on irRECIST by ICR or Modified irRECIST/irRC  
Phase 2 dose expansion:  
x
BOR and Duration of treatment post RECIST-PD based on irRECIST by ICR and Investigator 
x
BOR from start of treatment based on irRECIST by ICR or Modified irRECIST/irRC  
Tumor assessments using irRECIST by ICR or Modified irRECIST/irRC Criteria 
Phase 1 and 2 patients were initially assessed for tumor response by the Investigator using the Modified irRC 
criteria. However, the Protocol was amended to use Modified irRECIST criteria instead, from Protocol version 7 
(dated 15th December 2017) onwards. Patients initially assessed by Modified irRC and still ongoing tumor 
assessment at the time of implementation of Protocol version 7, were switched to the new Modified irRECIST 
criteria for all new tumor assessments. For those patients who “switched”, tumor response data from prior visits 
under Modified irRC were reviewed and updated in line with Modified irRECIST where possible.  
Note: To capture the Investigator assessed Modified irRECIST data a new ORRECIST eCRF page was implemented. 
This new page captures the total measurable tumor burden (TMTB - the sum of all measurable target lesions plus 
any new measurable lesions) and also the Modified irRECIST overall visit response. Appendix 2 in the Protocol, 
version 7 and onwards, give further details on the Modified irRECIST guidelines used by the investigator. 
To determine tumor-based endpoints based on Investigator assessed Modified irRECIST the following 
programming rules will be applied: 
1. Patients who completed tumor assessment prior to Protocol version 7 should have Modified irRC data for 
tumor assessment. These patients will be identified from not having any fields completed on the new 
ORRECIST eCRF page. 


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2. Patients who “switched” from Modified irRC to Modified irRECIST will be handled as follows: 
a. Where available, Modified irRECIST data from the ORRECIST eCRF page will be used to derive 
tumor based Modified irRECIST endpoints (using TMTB and overall response by Protocol-defined 
Modified irRECIST criteria) 
b. Prior to RECIST v1.1 progression, if Modified irRECIST data are not available (i.e. TMTB and/or 
overall visit response are missing on the ORRECIST eCRF page) then the RECIST v1.1 SOLD and 
RECIST v1.1 overall response will be substituted as the Modified irRECIST TMTB and Modified 
irRECIST overall visit response, respectively, as these will be exactly the same prior to RECIST v1.1 
progression. 
c.
On or after RECIST v1.1 progression, if no Modified irRECIST data are available then tumor 
response by Modified irRECIST will be considered missing/not done. 
d. In order to determine which patients could have RECIST v1.1 data substituted for Modified 
irRECIST prior to RECIST v1.1 progression, they must have at least one visit where the Modified 
irRECIST overall visit response is not equal to NE. This is to separate patients assessed by 
Modified irRECIST from the patients mentioned above who were only assessed per Modified irRC 
criteria. 
3. For new patients enrolled from Protocol version 7 onwards, Modified irRECIST data should be collected 
throughout the study. However, if Modified irRECIST data is missing for any tumor assessments then the 
above rules outlined above for the patients who “switched” will be used to derive the Modified irRECIST 
TMTB and the overall visit response. 
In addition to the Investigator assessed Modified irRECIST criteria, Phase 2 patients were also assessed centrally 
by ICR. ICR follows the published irRECIST guideline outlined in the Independent Review Charter which differs from 
the Protocol-defined Modified irRECIST criteria, where progression is defined differently (see below for further 
detail).  
Phase 2 patients will have their tumor response reported by ICR for irRECIST. Investigator assessments based on 
the Protocol-defined Modified irRECIST/irRC will be separately reported as supportive data for Phase 2 patients. 
Phase 1 patients will be reported based on Investigator assessed Modified irRECIST/irRC. Some ICR data may be 
available for some of the Phase 1 patients and any available ICR data will be listed. 
Note: the main differences between (a) Modified irRC criteria by Investigator, (b) irRECIST by ICR, and (c) Modified 
irRECIST by Investigator are: 
x
(a) Modified irRC uses measurement of longest diameter of both nodal and non-nodal lesions, 
whereas (b) irRECIST by ICR and (c) Modified irRECIST uses the longest diameter for non-nodal lesions 
and the short axis for nodal lesions in line with RECIST v1.1 criteria. Therefore, as described above, 
in the absence of the new TMTB field being completed for visits prior to RECIST-PD, the RECIST v1.1 


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SOLD value can be substituted instead for patients following (c) Modified irRECIST. 
x
(a) Modified irRC and (b) irRECIST by ICR require confirmation of progression at least 4 weeks apart 
(i.e. two visits of irPD at least 4 weeks apart), whereas (c) Modified irRECIST per the Protocol defines 
progression as a ≥ 20% increase in TMTB from the initial RECIST v1.1 progression, or unequivocal 
progression of non-target lesions or new non-measurable lesions. Therefore, as mentioned above, 
the definition of progression differs between (b) irRECIST by ICR and (c) Modified irRECIST by the 
Investigator. 
Derivation of Best overall Response using irRECIST by ICR or Modified irRECIST/irRC 
Criteria 
The same basic logic for deriving the best overall response (BOR) will be used as for the Primary Efficacy (see 
Section 14.1.2). It is the best response a patient has had following the date of first dose of study drug, but prior to 
either (i) disease progression according to the respective criteria*, (ii) the last evaluable tumor assessment in the 
absence of disease progression (including death), or (iii) starting any subsequent alternative cancer therapy 
including another investigational agent, whichever comes first. In other words, for patients who progress and 
subsequently have a response, the BOR will not include the response after a progression event. Furthermore, 
tumor assessments performed after initiating another anti-cancer therapy will not be included in the calculation 
of BOR. 
For (a) Modified irRC criteria by Investigator and (b) irRECIST by ICR, a patient’s BOR is derived in the following 
order, checking for best outcome before worst: 
1. irComplete Response (irCR): At least one confirmed visit response of irCR 
2. irPartial Response (irPR): If not irCR, at least one confirmed visit response of irPR. 
3. irStable Disease (irSD): If not irCR/irPR, at least one visit response of irSD (RECIST SD) or irSD (RECIST 
PD) recorded at least 8 weeks after date of first dose of study drug. Includes unconfirmed irCR or 
irPR recorded at least 8 weeks after date of first dose of study drug. 
4. irProgressive Disease - irPD (unconfirmed): If not irCR/irPR/irSD, an unconfirmed disease 
progression. Note: In absence of confirmed irPD, a BOR of unconfirmed irPD may be considered an 
irSD for reporting purposes.  
5. irProgressive Disease - irPD (confirmed): If not irCR/irPR/irSD, a confirmed disease progression or 
death in the absence of progression.  
6. Not-Evaluable (NE): No evidence of irCR, irPR, irSD, or irPD (regardless of confirmation). Either by 
default or the only visit response entered by the investigator is ‘Not evaluable’. 
For (c) Modified irRECIST by Investigator, a patient’s BOR is derived in the following order, checking for best 


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outcome before worst: 
1. irComplete Response (irCR): At least one confirmed visit response of irCR 
2. irPartial Response (irPR): If not irCR, at least one confirmed visit response of irPR. 
3. irStable Disease (irSD): If not irCR/irPR, at least one visit response of irSD (RECIST SD) or irSD 
(RECIST PD) recorded at least 8 weeks after date of first dose of study drug. Includes unconfirmed 
irCR or irPR recorded at least 8 weeks after date of first dose of study drug. 
4. irProgressive Disease - irPD (following RECIST 1.1 Progression): If not irCR/irPR/irSD, a disease 
progression (strictly at or after the first RECIST-PD) or death in the absence of progression.  
5. Not-Evaluable (NE): No evidence of irCR, irPR, irSD, or irPD (regardless of confirmation). Either 
by default or the only visit response entered by the investigator is ‘Not evaluable’. 
*Important note: For (a) Modified irRC and (b) irRECIST by ICR, disease progression has to be confirmed, whereas 
for (c) Modified irRECIST, progression does not require an unconfirmed irPD followed by a confirmed irPD.  
For (c) Modified irRECIST, response categories will be assigned as follows: 
x
irPD is defined as a ≥ 20% increase in TMTB compared to the initial RECIST v1.1 PD visit, or 
unequivocal progression of non-target lesions or new non-measurable lesions. For Modified irRECIST 
response, irPD will be assigned if the Investigator has recorded irPD as the overall visit response on 
the new ORRECIST eCRF page as “irProgressive Disease-irPD (following RECIST 1.1 Progression)”. 
o
In the absence of irPD on the ORRECIST eCRF page, deaths occurring strictly after the 
first RECIST-PD will also count towards irPD. 
o
Investigators may enter irPD, for clinical accuracy reasons, on the same date and visit 
as when RECIST v1.1 PD occurred. 
x
irCR, irPR, irSD, and NE are as described above for Modified irRC/irRECIST and as documented on the 
ORRECIST eCRF page. 
Further considerations for deriving BOR: 
•
*A special note: As stated above, prior to RECIST v1.1 progression, if (c) Modified irRECIST data 
are not available (i.e. TMTB and/or overall visit response are missing on the ORRECIST eCRF 
page) then the RECIST v1.1 overall response will be substituted as the Modified irRECIST overall 
visit response, as it will be exactly the same prior to RECIST v1.1 progression. On or after RECIST 
v1.1 progression, if no Modified irRECIST data are available then tumor response by Modified 
irRECIST will be considered missing/not done at these visits. 
•
For (a) Modified irRC and (b) irRECIST by ICR, if there is an unconfirmed irPD followed by a 
confirmed irPD with no evaluable responses in between, then the best overall response is 


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reported as a confirmed irPD. 
•
According to the eCRF for irRC, irSD can be either “irSD (RECIST SD)” or “irSD (RECIST PD)”. This 
is due to the criteria for SD and PD being different between RECIST and Modified irRC criteria, 
with irSD (RECIST SD) being a less-severe and better outcome. For the purposes of summarizing 
the BOR, these have been grouped into a single irSD category.  
•
Stable disease should be recorded at least 8 weeks ± 1 week, i.e. at least 49 days (to allow for 
the assessment window), after first dose. For determination of a best response of irSD of either 
kind, the earliest of the dates contributing towards a particular overall visit assessment will be 
used. The same goes for determining a best response of irSD for any unconfirmed irCR or irPR 
recorded at least 8 weeks after first dose. 
•
Per (a) Modified irRC criteria, the irPD definition for analysis of uni-dimensional or bi-
dimensional measurements is given in Protocol version 6 and previous versions. The investigator 
opinion of overall irRC visit response is used for analysis, rather than programmatically-derived 
overall visit responses.  
•
All data will be used up until the progression event (irPD or death in absence of irPD) that is used 
for the analysis. In other words, unconfirmed progressions per Modified irRC criteria/irRECIST 
by ICR, are not considered progression events, which means that the BOR may be after an 
unconfirmed progression for some patients. In absence of progression, data will be used up until 
the last evaluable assessment or starting any subsequent alternative cancer therapy including 
another investigational agent, whichever comes first.  
•
A maximum of two scheduled tumor assessment visits will be allowed to be missed before an 
irPD event is considered censored and hence will not contribute to the BOR derivation. See 
Section 14.1.2 of this SAP under Further considerations for deriving BOR for details. 
Confirmation of Overall Response Using irRECIST by ICR or Modified irRECIST/irRC 
Criteria  
Confirmation of irCR/irPR: 
Confirmation of response is required for declaring irPR or irCR in the ORR using (a) Modified irRC criteria by 
Investigator, (b) irRECIST by ICR, and (c) Modified irRECIST by Investigator, as it is for the analysis using RECIST v1.1 
criteria. A confirmed response is defined as an initial response (irCR or irPR) followed by a response at least 4 weeks 
later (for irCR this needs to be confirmed by irCR and for irPR this needs to be confirmed by either irPR or irCR). As 
for confirmation of response per RECIST v1.1 in Section 14.1.3, the initial overall visit assessment which showed a 
response will use the latest imaging date contributing towards a particular overall visit assessment. The same will 
be done for the confirmation overall visit assessment. 


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In the case where a patient has two non-consecutive visit responses of irPR, then, as long as the time between the 
2 visits of irPR is greater than 4 weeks and there is no PD between the irPR visits, the patient will be defined as a 
responder. For confirmation of response to count, visit responses of NE are allowed between visit responses of 
irCR to confirm an irCR, and likewise, visit responses of NE or irSD are allowed in between visit responses of 
irPR/irCR to confirm an irPR. For example, if a patient has visit responses of irCR, NE, irCR, then, as long as the time 
between the 2 visits of irCR is greater than 4 weeks, then a best response of irCR will be assigned. 
Tumor assessments will be performed every 8 weeks (±1 week) from C3D1 to C11D1, then every 12 weeks (± 1 
week) until disease progression or patient withdrawal. See Table 7-2 of the Protocol for the disease assessment 
collection plan. 
Confirmation of irPD: 
Disease progression (i.e. irPD) per (a) Modified irRC by Investigator and (b) irRECIST by ICR criteria does typically 
require confirmation. Once confirmed, the original date of disease progression entered is used as the date of irPD 
for analysis purposes. See Section below on PFS for deriving this date. 
x
Note: For (a) Modified irRC by Investigator, there are some cases where a single visit of automatic irPD 
confirmed is allowed without having to have a previous consecutive irPD unconfirmed assessment, e.g. if 
a patient develops new or significant worsening of brain metastases. In this case, the single date of 
confirmed disease progression entered by the Investigator is used as the date of irPD for analysis 
purposes. For irProgressive Disease - irPD (confirmed) to count as a visit response towards BOR in the 
analysis, all that is required is a single investigator-entered overall response of “irProgressive Disease-irPD 
(confirmed)”. This is irrespective of how many days are in between an unconfirmed irPD and confirmed 
irPD, and irrespective of if a previous consecutive irPD unconfirmed assessment exists. 
 
For (c) Modified irRECIST by Investigator, confirmation is not required, and therefore the earliest date irPD was 
recorded will be used to determine the date of progression. See Section 14.3.3.1 below under “The date of RECIST-
PD” for deriving this date. 

14.3.2. MISSING DATA METHODS FOR EXPLORATORY EFFICACY VARIABLES 
No adjustments for missing data will be made for any response data used for the Exploratory efficacy analyses. 
However, as per the Phase 2 primary efficacy analysis, an underlying assumption will be made such that missing 
tumor response data is not indicative of a complete or partial (objective) response, nor of stable disease or 
progressive disease. Therefore, any missing overall visit responses for tumor assessments are either considered as 
Not Evaluable in the calculation of the BOR or are ignored in any of the other calculations. 


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14.3.3. ANALYSIS OF EXPLORATORY EFFICACY VARIABLES 
BOR and Duration of Treatment Post RECIST-Progression (PD) 
A summary of BOR post RECIST-PD will be presented for irRECIST by ICR for Phase 2 Expansion only. Also, the 
duration of treatment post RECIST-PD will be presented, using both ICR data and Investigator opinion for RECIST-
PD, for both Phase 1 and 2. 
For the subset of patients in the FAS that continue treatment beyond RECIST v1.1 progression, the BOR will be 
derived in the same fashion as described above under Derivation of Best Overall Response using irRECIST by ICR or 
Modified irRECIST/irRC Criteria in Section 14.3.1.2. However, instead of being the best response following the date 
of first dose of study drug, the BOR post RECIST-PD will be defined as the best response a patient has had following 
the date of RECIST-PD, but prior to either (i) confirmed disease progression, (ii) the last evaluable tumor assessment 
in the absence of disease progression (including death), or (iii) starting any subsequent alternative cancer therapy 
including another investigational agent, whichever comes first. In other words, for patients who progress and 
subsequently have a response, the BOR will not include the response after a progression event according to the 
respective criteria. Furthermore, tumor assessments performed after initiating another anti-cancer therapy will 
not be included in the calculation of BOR. All other considerations above in the derivation of BOR are valid here. 
Only patients who have a date of last study drug administration greater than the date of RECIST-PD will be included 
in the analysis. 
In addition to the BOR post RECIST-PD, the duration of treatment post RECIST-PD will be calculated in a similar 
fashion to the overall duration of treatment (see Section 13.1):  
i.
Duration of treatment post RECIST-PD (days) = (date of last study drug administration – date of 
RECIST-PD). 
The date of RECIST-PD will be derived as per the progression date from the corresponding criteria: 
i.
irRECIST by ICR: RECIST-PD date will be based on the date of first RECIST progression recorded by 
ICR (see Section 14.1.2 under Further considerations for deriving BOR). 
A swimmer plot may be produced showing the duration of treatment for patients continuing treatment post-
RECIST-PD. 
A comparison summary listing of the BOR for each patient will be presented for all the following criteria side by 
side: 
x
BOR by RECIST v1.1 by ICR 
x
BOR by RECIST v1.1 by Investigator assessment 


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x
BOR by irRECIST by ICR  
x
BOR by Modified irRECIST (or Modified irRC in the absence of any Modified irRECIST data) by 
Investigator assessment 
x
BOR by irRECIST by ICR post RECIST-PD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15. SAFETY OUTCOMES 
All summary outputs for safety outcomes will be based on the SAF analysis set. All safety tables and listings will be 
presented according to APPENDIX 1 - Presentation of Treatment Groups. Safety tables in general will be presented 
by cohort (Phase 1 dose escalation cohorts by dose and the Expansion cohort, such that safety outcomes during 
the first two weeks of cycle 1 where the subject has received 20 mcg, or 30 mcg will not be distinguished from 
safety outcomes following the escalated dose on C1D15. However, listings will show the actual dose at the time of 
the AE. Additional plots (as described further below), such as adverse event toxicity plots, may address the timing 
of safety outcomes. 
Unless otherwise stated, the overall observation period will be divided into 3 mutually exclusive segments as 
follows: 
x
Pre-treatment period: from day of patient’s informed consent (or pre-screening informed consent) 
to the time of the first dose of study drug 
x
On-treatment/follow-up period: from immediately after the first dose of study drug to 90 days after 
last dose of study drug 
x
Post-treatment/follow-up period: starting at Day 91 after last dose of study drug  
For domains such as concomitant medications and adverse events, definitions of concomitance and treatment 
emergence are included in the associated sections of this SAP. 
15.1.
DOSE LIMITING TOXICITIES 
The primary variable is the incidence (number) of dose limiting toxicities (DLTs) in the Phase 1 dose escalation part 
of the study. The DLT observation period for the Phase 1 cohorts is the first cycle during IMCgp100 dosing (C1D1 
until C1D28). 
A DLT is defined as an adverse event or abnormal laboratory value that occurs within the first cycle of treatment 
and is assessed as (1) having a suspected relationship to study drug, (2) being unrelated to disease, disease 
progression, inter-current illness, or concomitant medications, and (3) meets any of the criteria included in Table 
6-3 of the Protocol. DLTs are recorded on the Dose-Limiting Toxicity eCRF page and additionally filled in on the 
Adverse Event/Serious Adverse Event eCRF page. 
Further information on a DLT for this study is given in Section 6.4 of the Protocol. 
The primary objective is to identify the MTD and/or the RP2D of IMCgp100 in the weekly intra-patient escalation 


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dosing regimen. 
The MTD is defined as the highest dose level with an observed incidence of DLT in fewer than 33% of the patients 
enrolled in a cohort level. If all evaluated dose levels demonstrate an observed incidence of DLT in fewer than 33% 
of patients, the MTD has not been reached. If this proves to be the case, then a total of 6 patients will be treated 
at the highest dose tested to gain additional safety data before proceeding to the dose-expansion part of the study. 
If a DLT occurs at the MTD, a total of 6 patients must be treated at the MTD.  
The RP2D-IE will be defined as the dose level selected for testing in the expansion cohort by the Study Team, based 
on all available safety, tolerability, PK and pharmacodynamic data. The MTD and RP2D-IE may not be the same 
dose level; the RP2D-IE will be the same dose or a lower dose than an identified MTD. If the MTD and RP2D are 
different, the RP2D-IE will be implemented in the expansion cohort. A minimum of 6 patients will be treated at the 
identified RP2D-IE for the DLT period before the expansion cohort with this dose can begin enrollment. 
The determination of the MTD and RP2D-IE is a clinical decision and is not impacted by any analysis performed by 
IQVIA Biostatistics. For further details of dose escalation guidelines, including the determination of the MTD and 
RP2D-IE, refer to Section 6.3.4 of the Protocol. The primary and final analysis provided by IQVIA Biostatistics will 
include a table of the number of DLTs by dose level for the SAF. DLTs will also be listed. 
15.2.
ADVERSE EVENTS 
Adverse Events (AEs) will be coded using Medical Dictionary for Regulatory Activities (MedDRA) central coding 
dictionary, using 22.0 or later (i.e. a later version MedDRA may be available and used at the time of coding for the 
reporting period). 
Treatment-emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity from the date 
of first dose (regardless of time) up until 90 days after the last dose of study drug or until start of subsequent 
alternative cancer therapy, whichever occurs first. Only alternative cancer therapies with start dates that are 
greater than the date of last dose of study drug (i.e. subsequent), are considered. Therefore, the treatment-
emergence period will be at a minimum up until the date of last dose of study drug + 1. 
The start date of subsequent alternative cancer therapy is derived as the earliest start date from (i) alternative 
cancer therapies entered on the Prior and Concomitant Medications eCRF page (see Section 12.1) which occur 
after the date of last dose of study drug, and (ii) from therapies entered on the Antineoplastic therapies since 
discontinuation eCRF page (see Section 12.2). See APPENDIX 2 for handling of partial dates for AEs and subsequent 
alternative cancer therapies. In the case where it is not possible to define an AE as treatment-emergent or not, the 
AE will be classified by the worst case; i.e. treatment-emergent.  
An overall summary of number of patients within each of the categories described in the sub-section below, will 
be provided as specified in the templates.  


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An AE Listing will include TEAEs and Non-TEAEs, including those from the screening and post-treatment periods 
which will be flagged as such. Only TEAEs will be summarized. 
AE Structure as Recorded in the eCRF: 
AEs will be recorded in the eCRF with a new adverse event record each time the severity of an adverse event 
changes. This means each unique AE record is not necessarily a distinct event. Where a single event is split across 
multiple records due to a changing severity grade, these split adverse event records require being grouped using 
a dataset flag in order to identify the single event for a subject. This will be handled as follows: 
x
Adverse events that do not change in severity over the course of their duration will be recorded as single 
event records in the eCRF and require no further manipulation post collection. 
x
Adverse events that do change in severity over the course of their duration will be grouped using the 
following algorithm: 
o
For a given subject, if the same AE Preferred Term exists across two or more records where the 
AE Stop Date (+1 day) of the first record equals the AE Start Date of the next record, and so on, 
or if there is overlap in the dates for the records, these two or more records will be ‘grouped’ in 
order to flag they are of the same unique AE. 
Notes:  
x
Severity is defined using the NCI CTCAE version 4.03 Grades as recorded on the eCRF. 
x
AE records with partial dates will not be grouped. 
x
This ‘grouping’ does not entail creating any new combination records nor does it mean truncating 
the existing records. A flag in the AE dataset will simply be used to indicate these records are of the 
same unique AE. 
x
Grouped AEs will be counted as a single event in event-level summaries but will be presented 
separately (as recorded in the CRF) in the listings.  
x
For calculating AE durations in a data listing, the duration of each event will be calculated at each 
distinct severity. Also, the total duration will be calculated for AEs that change in severity over the 
course of their duration. The total duration will be calculated as the last AE Stop Date - first AE Start 
Date + 1 in the grouped records for a unique AE. If the last of the AE records within same group is 
ongoing, then the total duration will be calculated as the last AE Start Date - first AE Start Date + 1. In 
this case, the total duration will be concatenated with '+' to imply that the total duration is at least 
the calculated number of days. 
x
The definition of a treatment-emergent AE will be handled appropriately for AEs split across each 
distinct severity level. Specifically, only when an AE worsens in severity within the timeframe from 


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the date of first dose (regardless of time) up until 90 days after the last dose of study drug or until 
start of subsequent alternative cancer therapy, whichever occurs first, will it be defined as treatment-
emergent. A worsening severity is defined as changing from a less severe (lower) CTCAE grade to a 
more severe (higher) CTCAE grade. 
15.2.1. ALL TEAES  
Incidence of TEAEs by subject count, in addition to number of total TEAEs, will be presented by System Organ Class 
(SOC) and Preferred Term (PT) and also broken down further by maximum severity. 
Severity 
Severity is based on NCI CTCAE v.4.03 grades and classed as mild, moderate, severe, life threatening, or death 
related to AE (increasing severity), as represented by Grades 1-5, respectively. TEAEs starting after the first dose 
of study drug with a missing severity will be classified as ‘missing’. If a patient reports the same AE more than once 
within that SOC/PT, the AE with the worst-case severity will be used in the corresponding severity summaries. In 
determining maximum severity, response values will be ranked in order from minimum severity to maximum 
severity as Missing, Grade 1, Grade 2, Grade 3, Grade 4, and Grade 5 (as values: ‘missing’, ‘mild’, ‘moderate’, 
‘severe’, ‘life threatening’, and ‘death related to AE’).  
A summary table will present TEAEs, showing number of subjects (%) for all grades (including missing grades) and 
grades ≥ 3 for each SOC/PT. This summary table will also be repeated for TEAEs related to IMCgp100. 
Relationship to Study Drug (IMCgp100) 
Relationship, as indicated by the investigator, is classed as unrelated or related.The categories ‘possibly’ related 
or ‘related’ will be pooled to create the ‘related’ category. TEAEs with a missing relationship to study drug will be 
regarded as ‘missing’. 
15.2.2. TEAES LEADING TO DOSE INTERRUPTION  
TEAEs leading to dose interruption will be identified by using the “Action taken with the study drug” variable 
collected on the eCRF, where the variable is equal to ‘Dose interrupted’. These will be flagged in the listing. 
15.2.3. TEAES LEADING TO DISCONTINUATION OF STUDY DRUG 
TEAEs leading to permanent discontinuation of study drug will be identified by using either (1) the “Action taken 


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with the study drug” variable collected on the eCRF, where the variable is equal to ‘Drug permanently 
discontinued’, or (2) the “Did the AE cause the patient to discontinue from the study medication?” variable 
collected on the eCRF, where the variable is equal to ‘Yes’. These will be flagged in the listing.  
15.2.4. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as ‘Yes’ in response to the “Does the Adverse Event meet 
seriousness criteria?” question on the AE/SAE page of the eCRF. A summary of serious TEAEs by SOC and PT will 
be presented. These include both deaths as an outcome of SAEs and non-fatal SAEs. Deaths as an outcome of SAEs 
are those events which have a severity recorded as ‘Grade 5 - Death related to AE’ and are marked as serious.  
A listing of SAEs (including deaths as an outcome of SAEs) will also be created. 
A summary of serious TEAEs and Serious TEAEs related to IMCgp100 by SOC and PT will be presented. 
15.2.5. ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to death are defined in Section 15.2.4. These events will be summarized as part of the SAE summary 
table.  
Any AE leading to death will be also listed in a separate data listing from SAEs.  
15.2.6. ADVERSE EVENTS OF SPECIAL INTEREST  
Incidence of TEAEs of Special Interest for IMCgp100 will be presented by the TEAE of special interest category and 
PT. The investigator response to the question ‘Is it an adverse event of special interest?’ will not be reported. Based 
on data from the ongoing and completed clinical trials, the Sponsor considers the following to be IMCgp100 
adverse events of special interest (AESI): 
x
Cytokine release syndrome (CRS) 
x
Rash  
x
LFT (Liver Function Tests) elevation 
Due to evolution in grading and terminology there may likely be under-reporting of CRS as an AE, the incidence 
and severity of CRS will be based on a medical review utilizing the ASTCT consensus grading for CRS (Lee, et. al, 
2019). By incorporating AE, concomitant medication, and vital sign data, a determination will be made as to 


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whether CRS occurred after each patient’s dose and, if so, at what grade.  Using this approach, the incidence of 
CRS as an AESI will not match reports of CRS as an AE in AE-based tables.   
Rash will be identified using a medically-approved list of PTs provided by the Sponsor. See APPENDIX 6 for details.   
LFT elevation will be based on the Standard MedDRA Queries (SMQs) “Drug related hepatic disorders – 
comprehensive search.”  Both Narrow and Broad scope terms will be considered.   
Incidence of TEAEs for AESI will also be summarized broken down by maximum severity (Total, Grade 1, Grade 2, 
Grade 3, Grade 4, Grade 5) for the AESI category. 
Toxicity plots will be produced for AESIs to show the frequency and timing, in respect to when the events occurred 
while patients were on-treatment. 
15.2.7. ADVERSE EVENTS BEYOND DISEASE PROGRESSION 
A summary of the number of patients with TEAEs that occurred post RECIST-Progression (PD) by Investigator 
assessment will be presented by SOC, PT, and CTCAE grade ≥ 3.  
In this case, the treatment-emergence definition is altered for “TEAEs occurring post RECIST-PD” such that any AEs 
that started or worsened in severity from the date of first RECIST-PD up until 90 days after the last dose of study 
drug, are included. Therefore, the following are included: 
x
TEAEs that have an AE start date ≥ first RECIST-PD date by Investigator assessment, or 
x
TEAEs that are ongoing at RECIST-PD date by Investigator assessment that have worsened post RECIST-
PD 
o
Note: The definition of a “TEAEs occurring post RECIST-PD” will be handled appropriately for AEs 
split across each distinct severity level. Specifically, only when an AE worsens in severity within 
the timeframe from the date first RECIST-PD up until 90 days after the last dose of study drug or 
until start of subsequent alternative cancer therapy, whichever occurs first, will it be included. A 
worsening severity is defined as changing from a less severe (lower) CTCAE grade to a more 
severe (higher) CTCAE grade. 
15.3.
DEATHS 
If any patients die during the study as recorded on the Death page of the eCRF, the information will be summarized 
in a table by primary reason for death and presented in a data listing. 


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15.4.
LABORATORY EVALUATIONS 
Results from local laboratory data will be included in the reporting of this study for Hematology, Chemistry, 
Coagulation, Urinalysis, Thyroid, and Cytokines. All laboratory parameters assessed for safety purposes will be 
evaluated locally. A list of laboratory assessments to be included in the outputs is included in Table 7-5 of the 
Protocol, Section 7.3.7. The treatment periods to be used for reporting laboratory data are defined in Section 15. 
Presentations will use International System of Units (SI Units). 
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), or 
“> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
Handling of retests and unscheduled measurements for laboratory results is included in Section 6.3 of this SAP. 
The following summaries will be provided for laboratory data. These summaries will be repeated for hematology, 
biochemistry (chemistry, coagulation, inflammatory analytes, thyroid function and cytokines), and urinalysis: 
x
Actual and change from baseline by visit (for quantitative measurements) may be presented. 
x
Shift from baseline to the worst on-treatment/follow-up value according to NCI CTCAE grading 
system for quantitative measurements, as well as for urinalysis categorical measurements. 
o
For measurements that have a National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) grading system, ‘worst’ will be defined as the maximum (i.e. most 
severe) Grade obtained during treatment; see Section 15.4.3  below. A missing value for Grade 
due to a missing laboratory value is considered to be the least severe. A special note: For 
laboratory tests that have CTCAE grades defined for both a lower and higher level of extremity, 
separate shift from baseline summaries will be presented for each extreme of abnormality, e.g. 
(i) Lymphocytes Absolute Count – Low and (ii) Lymphocytes Absolute Count – High. See Section 
15.4.3 below for all relevant tests. 
o
For urinalysis categorical measurements, ‘worst’ will be defined as the maximum (i.e. most 
severe) result, where the results ranked in order from minimum severity to maximum are: ‘Not 
done’, ‘NEG’, ‘+’, ‘++’, and ‘+++’. 
x
Listing of all clinically relevant laboratory data with values flagged to show the corresponding NCI 
CTCAE grades and the classifications relative to the laboratory normal ranges. 
For both hematology and biochemistry, the following plots will be produced: 
x
Scatter plot of worst on-treatment/follow-up value versus baseline value, with values expressed as 


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multiples of the lower limit normal or upper limit normal. Note that parameters will be presented 
separately for both above and below the normal range, since ‘worst’ will be defined as both extremes 
of abnormality. 
x
Plot of patient profiles over time for all patients with at least one CTCAE grade ≥ 3 – for specific 
Sponsor-decided laboratory tests only 
x
Plot of individual patient profiles for patients with at least one CTCAE grade ≥ 3 – for specific Sponsor-
decided laboratory tests only 
To assess potential drug-induced liver injury (DILI) using Hy’s Law, the following summaries for liver function tests 
will be produced: 
x
Incidence of patients with Alanine aminotransferase (ALT) or Aspartate transaminase (AST) ≥ 3xULN 
and total bilirubin ≥ 2xULN within specified time intervals. The time intervals that will be summarized 
are the following: 
o
ALT/AST and total bilirubin elevation results at any time during on-treatment/follow-up. 
o
ALT/AST elevation result within one week (+/- 7 days) of total bilirubin elevation result, during 
on-treatment/follow-up.  
o
ALT/AST elevation result within one day (+/- 1 day) of total bilirubin elevation result, during on-
treatment/follow-up.  
o
ALT/AST elevation results within one day (+/- 1 day) of total bilirubin elevation results with a 
duration of ≥ 7 days, during on-treatment/follow-up. Duration is calculated as consecutive days 
(subsequent laboratory date – previous laboratory date) where the elevated levels of both (ALT 
or AST ≥ 3xULN) and total bilirubin ≥ 2xULN are maintained, without going below the potential 
Hy's Law criteria. 
x
A scatter plot of worst on-treatment/follow-up value for ALT versus total bilirubin, with values 
expressed as multiples of the upper limit normal will be produced. This scatterplot will be repeated 
for AST versus total bilirubin. 
15.4.1. LABORATORY SPECIFIC DERIVATIONS 
The following laboratory parameters will be derived as follows: 


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x
Corrected Calcium [mmol/L]* = Serum Calcium [mmol/L] + 0.02 (40 - Serum Albumin [g/L]) 
o
*This correction will only be applied for records at the patient/visit level where albumin is less 
than the lower limit of normal. For records where albumin is greater than or equal to the lower 
limit of normal, no correction will be applied, and the Corrected Calcium value will equal the 
calcium (uncorrected) value, as collected on the eCRF. 
o
Note: The reference ranges for Corrected Calcium will be derived on a patient by patient, visit by 
visit level, as the same reference ranges collected locally for calcium (uncorrected), which is a 
parameter collected directly from eCRF. 
All other laboratory parameters are available from the data collected on the eCRF. Local laboratory results will be 
converted into SI units and presentations will use SI Units. 
15.4.2. LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
The following laboratory tests do not have grades defined by NCI CTCAE: 
Hematology: 
x
Hematocrit 
x
Absolute basophils 
x
Absolute eosinophils 
x
Absolute monocytes 
Biochemistry: 
x
Bicarbonate 
x
Chloride 
x
Lactate dehydrogenase (LDH) 
x
C-reactive protein (CRP) 
x
Blood urea nitrogen 


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x
Urea 
x
Total T3 (Triiodothyronine) – only for some patients; list only 
x
Free T4 (Thyroxine, Free) 
x
Thyroid stimulating hormone (Thyrotropin) 
x
Prothrombin time (in seconds) – when collected in %; list only 
x
Gamma-interferon -  only for some patients; list only 
x
Interleukein-6 -  only for some patients; list only 
Urinalysis: 
x
Macroscopic panel (dipstick) (bilirubin, blood, glucose, ketones, pH, protein, specific gravity, white 
blood cells) 
For these laboratory tests, results will be graded by the low/normal/high classifications based on laboratory normal 
ranges. In this case, quantitative laboratory measurements will be compared with the relevant laboratory 
reference ranges in SI units and categorized as: 
x
Low: Below the lower limit of the laboratory reference range.  
x
Normal: Within the laboratory reference range (upper and lower limit included). 
x
High: Above the upper limit of the laboratory reference range. 
The lower and upper limit will be referred to in outputs as LLN = Lower Limit Normal and ULN = Upper Limit Normal, 
respectively. 
15.4.3. NCI CTCAE GRADING FOR LABORATORY DATA 
Laboratory measurements will be graded by the study team using NCI CTCAE version 4.03 as defined in the 
following link: https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf     
Laboratory tests covered by NCI CTCAE are as follows (found under ‘Investigations’ in the link above unless 
otherwise specified): 


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Hematology: 
x
Hemoglobin – presented in shift tables as ‘Low’ and ‘High’ 
x
White blood cell count (Leukocytes) – presented in shift tables as ‘Low’ and ‘High’ 
x
Platelet count 
x
Absolute neutrophils count 
x
Absolute lymphocyte count – presented in shift tables as ‘Low’ and ‘High’ 
Biochemistry: 
x
Creatinine 
x
Sodium (see hypernatremia/hyponatremia) – presented in shift tables as ‘Low’ and ‘High’ 
x
Potassium (see hyperkalemia/hypokalemia) – presented in shift tables as ‘Low’ and ‘High’ 
x
Albumin (see hypoalbuminemia) 
x
Total bilirubin (and direct/indirect) 
x
Alkaline phosphatase 
x
ALT 
x
AST 
x
Magnesium (see hypermagnesemia/ hypomagnesemia) – presented in shift tables as ‘Low’ and ‘High’ 
x
Corrected Calcium (see hypercalcemia/hypocalcemia) – see Section 15.4.1– presented in shift tables 
as ‘Low’ and ‘High’ 
x
Glucose (see hyperglycemia/hypoglycemia) – presented in shift tables as ‘Low’ and ‘High’ 
x
Amylase 


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x
Inorganic phosphate (see hypophosphatemia) 
x
Lipase 
x
Prothrombin international normalized ratio (see INR increased) 
x
Activated partial thromboplastin time 
For laboratory tests covered by NCI CTCAE, a grade 0 will be assigned for all non-missing values not graded as 1 or 
higher. Any missing laboratory value will consequently have a missing CTCAE Grade. 
If the NCI CTCAE version 4.03 documentation above, requires LLN/ULN, to derive Grade 1, then follow the rules 
below: 
For LLN: 
x
If LLN is above or equal to the lower value of the range for the Grade 1, then continue with the 
process as specified in the NCI CTCAE version 4.03 documentation. 
x
If LLN is below the lower value of the range for the Grade 1 then check if the laboratory test value is 
equal to the lower value, if yes set this to Grade 1. If the laboratory test value is above the lower 
value of the range for the Grade 1, then set to Grade 0. Else grade as per the rules for Grade 2 
onwards. 
For ULN: 
x
If ULN is below or equal to the higher value of the range for the Grade 1, then continue with the 
process as specified in the NCI CTCAE version 4.03 documentation. 
x
If ULN is above the higher value of the range for the Grade 1 then check if the laboratory test value 
is equal to the higher value, if yes set this to Grade 1. If the laboratory test value is below the higher 
value of the range for the Grade 1, then set to Grade 0. Else grade as per the rules for Grade 2 
onwards. 
 
 
 


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15.5.
ECG EVALUATIONS 
Results from the Electrocardiogram (ECG) as recorded by the Investigator on the eCRF will be included in the 
reporting of this study. The treatment periods to be used for reporting ECG data are defined in Section 15. 
The following ECG parameters will be reported for this study: 
x
PR Interval (msec) 
x
QRS Interval (msec) 
x
QT Interval (msec) 
x
QTcB Interval (msec) 
x
QTcF Interval (msec) 
x
Overall assessment of ECG (Investigator’s judgment): 
o
Normal 
o
Abnormal, Not Clinically Significant (ANCS) 
o
Abnormal, Clinically Significant (ACS) 
The following summaries will be provided for ECG data: 
x
Shift from baseline to the worst on-treatment/follow-up value according to the predefined criteria 
for varying degrees of abnormality for prolonged QTcB and QTcF. Section 15.5.2 below states the 
exact criteria used to grade ECGs. A value below the lowest threshold of concern, i.e. ≤ 450 msec, will 
be assigned a value of ‘Normal’. The ‘worst’ on-treatment/follow-up value will be defined as the 
maximum (i.e. most severe) abnormality criterion obtained during treatment. A missing value due to 
a missing ECG value is considered to be the least severe. 
x
Shift from baseline to worst on-treatment/follow-up value for PR and QRS interval abnormalities. 
Normal range criteria will be used to define ‘worst’ as both extremes of abnormality (lowest and 
highest); see Section 15.5.2 below. A missing value due to a missing ECG value is considered to be the 
least severe. 
Values meeting markedly abnormal criteria will be flagged in the listing. 


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15.5.1. ECG SPECIFIC DERIVATIONS 
x
QTcF Interval (msec) post-baseline is not collected directly on the eCRF. Therefore, at all visits after 
screening, ܳܶܿܨ will be derived using ܳܶ and ܳܶܿܤ as collected in milliseconds from the 
Electrocardiogram – Study eCRF page: 
x
Convert ܳܶ and ܳܶܿܤ from milliseconds to seconds: 
o
ܳܶሺሻൌܳܶሺሻȀͳͲͲͲ 
o
ܳܶܿܤሺሻൌܳܶܿܤሺሻȀͳͲͲͲ 
x
Calculate ܳܶܿܨሺሻൌ
ொ்
ೂ೅
ೂ೅೎ಳ
మȀయൌܳܶሺሻଵȀଷൈܳܶܿܤሺሻଶȀଷ 
x
Convert ܳܶܿܨ in seconds to milliseconds: 
x
ܳܶܿܨሺሻൌܳܶܿܨሺሻൈͳͲͲͲ 
Note that this will be done for both pre-dose and 1-hour (±5 min) post dose ECG measurements taken post 
baseline. 
15.5.2. ECG MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative ECG measurements will be identified in accordance with the following predefined 
criteria for varying degrees of abnormality for prolonged QTc (based on ICH – E14 standard ranges, 
https://database.ich.org/sites/default/files/E14_Guideline.pdf. 
For rating the ‘worst’ on-treatment/follow-up value for QTcB and QTcF absolute values, the following categories will 
be used based on the varying degrees of abnormality above, in the order of least to most severe (top to bottom): 
 
x
Missing result 
x
≤ 450 msec (i.e. ‘Normal’) 
x
>450-480 msec 


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x
>480-500 msec 
x
>500 msec 
For rating the ‘worst’ on-treatment/follow-up value for QTcB and QTcF change from baseline values, the following 
categories will be used based on the varying degrees of abnormality above, in the order of least to most severe 
(top to bottom): 
x
Missing result 
x
≤ 30 msec increase from baseline 
x
30 to ≤ 60 msec increase from  baseline 
x
> 60 msec increase from baseline 
For rating the ‘worst’ on-treatment/follow-up value for PR and QRS intervals the values will be graded by the 
following low/normal/high classifications based on the normal range criteria, in order of least to most severe (top 
to bottom):  
 
PR Interval: 
x
Missing result 
x
<120 msec (i.e. ‘Low’) 
x
120-200 msec (i.e. ‘Normal’) 
x
>200 msec (i.e. ‘High’) 
QRS interval: 
x
Missing result 
x
<80 msec (i.e. ‘Low’) 
x
80-120 msec (i.e. ‘Normal’) 
x
>120 msec (i.e. ‘High’) 


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15.6.
VITAL SIGNS 
The treatment periods to be used for reporting vital signs data are defined in Section 15. The following Vital Signs 
measurements will be reported for this study: 
x
Systolic Blood Pressure (mmHg) 
x
Diastolic Blood Pressure (mmHg) 
x
Respiratory Rate (breaths/min) 
x
Pulse Rate (bpm) 
x
Temperature (⁰C) 
x
Weight (kg) 
All measurements apart from weight are taken in a sitting position after at least 5 minutes rest. 
The following summaries will be provided for vital signs data: 
x
Shift from baseline to the worst on-treatment/follow-up value (for all quantitative measurements) 
according to the predefined criteria for varying degrees of abnormality. Section 15.6.2 below states 
the exact criteria used to grade vital signs. The ‘worst’ on-treatment/follow-up value will be defined 
as the maximum (i.e. most severe) abnormality criterion obtained during treatment.  A missing value 
due to a missing vital signs value is considered to be the least severe. 
o
Note: Systolic blood pressure will have separate shift from baseline summaries presented for (i) 
highest and lowest absolute values and (ii) maximum increase and decrease changes from 
baseline values.   
x
The following plots will be produced twice separately for: 1. All assessment time points and 2. All 
assessments after first dose of study drug up to a specific period of time.   
o
Plot of patient profiles over time for all patients with at least one hypotension or cytokine release 
syndrome event of CTCAE grade ≥ 3 
o
Plot of patient profiles over time for all patients with at least one SBP decrease from baseline ≥ 
35mmHg 


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Values meeting markedly abnormal criteria will be flagged in the listing. 
15.6.1. VITAL SIGNS SPECIFIC DERIVATIONS 
Weight can be entered on the eCRF in kg or lbs. Any weight assessments entered in lbs will be converted to kg by 
dividing by 2.205. 
15.6.2. VITAL SIGNS MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative Vital Signs measurements will be identified in accordance with the following 
predefined markedly abnormal criteria: 
Variable 
Unit 
Low 
High 
SBP 
mmHg 
< 90 mmHg 
Post-baseline:  
Decrease from baseline of: 
(1) < 15 mmHg 
(2)  ≥ 15 mmHg and < 35 mmHg 
(3)  ≥ 35 mmHg 
CTCAE Grade 1: 120 to 139 mmHg 
CTCAE Grade 2: 140 to 159 mmHg 
CTCAE Grade 3: ≥ 160 mmHg 
 
Post-baseline:  
Increase from baseline of: 
(1) < 15 mmHg 
(2)  ≥ 15 mmHg and < 35 mmHg 
(3)  ≥ 35 mmHg 
DBP 
mmHg 
< 60 mmHg 
 
CTCAE Grade 1: 80 to 89 mmHg 
CTCAE Grade 2: 90 to 99 mmHg 
CTCAE Grade 3: ≥ 100 mmHg 


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Variable 
Unit 
Low 
High 
Respiratory 
Rate  
breaths/ 
min 
<10 breaths/min  
 
 
Baseline: ≥ 20 breaths/min 
Post-baseline: Do 1 of following: 
(1) If Low/Normal at baseline:  
≥ 20 breaths/min OR 
change from baseline ≥ 10 
breaths/min 
(2) If High at baseline:  
≥ 20 breaths/min 
Pulse rate 
bpm 
Baseline: ≤ 60 bpm 
Post-baseline: Do 1 of following: 
(1) If Normal/High at baseline:  
≤ 50 bpm AND 
change from baseline ≤ -15 bpm 
(2) If Low at baseline:  
≤ 50 bpm 
Baseline: ≥ 100 bpm 
Post-baseline: Do 1 of following: 
(1) If Low/Normal at baseline:  
≥ 100 bpm AND 
change from baseline ≥ 15 bpm 
(2) If High at baseline:  
≥ 100 bpm 
Body 
Temperature 
˚C 
N/A 
CTCAE Grade 1: 38.0 – 39.0 ˚C 
CTCAE Grade 2: >39.0 – 40.0 ˚C 
CTCAE Grade 3: >40.0 ˚C for 
consecutive ≤ 24 hours 
CTCAE Grade 4: >40.0 ˚C for 
consecutive >24 hours 
Weight 
kg 
Baseline: N/A 
Post-baseline: percentage change 
from baseline ≤ -10.0 % 
Baseline: N/A 
Post-baseline: percentage change 
from baseline ≥ 10.0 % 
Note: Since Weight at baseline has no Low or High markedly abnormal criteria, the baseline value will be 
represented in summary tables and listings as “Baseline”. For other vital signs variables and weight post-baseline, 


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STATISTICAL ANALYSIS PLAN: 
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a value that is not Low nor High will be represented as “Normal”. 
15.7.
PHYSICAL EXAMINATION 
Physical Examination results will be listed, and abnormalities will be flagged. 
Ophthalmologic and audiologic assessment data will be separately listed and abnormalities will be flagged. 
15.8.
OTHER SAFETY ASSESSMENTS 
15.8.1. ECOG PERFORMANCE STATUS 
Eastern Cooperative Oncology Group performance status is collected at screening, on Day 1 of every odd-
numbered cycle and at the EOT visit. The status is determined as follows at each visit: 
x
Grade 0 = Fully active, able to carry on all pre-disease performance without restriction 
x
Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature (e.g., light house work, office work) 
x
Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
x
Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
x
Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
x
Grade 5 = Dead 
ECOG performance status at each visit will be listed. 
Also, a summary will be presented for the shift from baseline to the best on-treatment/follow-up value and the 
shift from baseline to the worst on-treatment/follow-up value. Here, ‘best’ is defined as the lowest ECOG grade 
(Grade 0 being the lowest). Likewise, ‘worst’ is defined as the highest ECOG grade (Grade 5 being the highest). A 
missing value due to a missing ECOG performance status is the last value considered in either the ‘best’ or ‘worst’ 
case. 
 


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PROTOCOL IMCgp100-102 
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16.
 PHARMACOKINETICS  
Samples for pharmacokinetic analysis are drawn at many visits and at the following time-points: pre-dose, end of 
infusion, 4-hour post dose, 8-hour post dose, and 12-24-hour post dose. See Table 7-7 in the Protocol, Section 
7.3.8 for the schedule of PK assessments.  
16.1.1. PK VARIABLES & DERIVATIONS 
The PK parameters to be derivedand analyzed by Immunocore and/or a third-party vendor and summarized/listed 
by IQVIA. These are given in Table A below: 
Table A Pharmacokinetic Parameters to be Analyzed 
AUClast 
The area under the curve (AUC) from time zero to the last measurable concentration 
sampling time (tlast) (mass × time × volume-1) 
AUCinf 
The AUC from time zero to infinity (mass × time × volume-1) for Cycle 1 Day 1 only 
AUCtau 
The AUC over the dosing interval for Cycle 1 Day 15 only 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass × volume-1) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time) 
T1/2 
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives 
CLSS 
The clearance steady state (dose/ AUCtau) for Cycle 1 Day 15 only 
CL 
The total body clearance of drug from the plasma (volume × time-1) for Cycle 1 Day 1 only 
Vz 
The apparent volume of distribution during terminal phase (associated with λz) (volume) 
 
Additional parameters may be calculated as deemed necessary based on the final data available.  
 


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16.1.2. ANALYSIS OF PK 
The SAF will be used for all PK summaries and listings. The following summaries/analyses will be provided for PK 
parameter data: 
x
Summary of descriptive statistics of all derived parameters for IMCgp100. The statistics to be 
presented include the arithmetic and geometric mean, median, standard deviation (Std), coefficient 
of variation (%CV), geometric mean ± standard deviation, minimum, and maximum.  
x
Summary of descriptive statistics for the collected pharmacokinetic concentrations for IMCgp100 in 
pg/mL. 
x
Concentrations profile plots for individual patients by Phase and cohort. 
x
Arithmetic mean concentration profile plots by Phase and cohort (coloured line for each 
cohort/expansion) with errors bars.  
x
Plot of pre-dose concentrations versus End of infusion at Day 1 of each Cycle. 
x
Listings of pharmacokinetic parameters and concentrations. 
The following considerations will be taken into account: 
x
Concentration values below lower limit of quantitation (LLOQ) will be handled as zero in summary 
statistics and reported as is in the data listing of collected PK concentrations. The LLOQ for IMCgp100 
is 25 pg/mL. Please note the following: 
o
If the arithmetic mean is below the LLOQ value (i.e. < 25 pg/mL) then the arithmetic mean will 
be displayed as ‘<LLOQ’ in the summary table. The same holds for the following statistics: min, 
max, and median. The standard deviation and %CV will be reported as Not Calculable (NC).  
o
Concentration values and arithmetic means that are below the LLOQ value will be set to 12.5 
pg/mL (half the LLOQ value) in the both the concentration and arithmetic mean profile plots.  
x
The geometric mean will be calculated as the exponential of the arithmetic mean calculated from 
data on a natural log scale.  
o
The geometric mean will only be calculated at timepoints where all patients have concentration 
values above the LLOQ.  


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Page 80 of 131
x
Geometric mean ± standard deviation will be calculated as exp[μ±s]), where μ is arithmetic mean 
calculated from data on a natural log scale, and s is the standard deviation of the data on a natural 
log scale. 
o
The geometric mean ± standard deviation will only be calculated at timepoints where all patients 
have concentration values above the LLOQ. 
x
The %CV is calculated as (arithmetic standard deviation / arithmetic mean) ൈͳͲͲ.   
x
Since Tmax is generally evaluated by a non-parametric method, only the median, minimum, and 
maximum will be presented for this parameter. 
The concentration-/AE-immunogenicity relationship will be explored graphically and tabulated to characterize a 
relationship between the changes from confirmed immunogenicity presence and serum concentration of 
IMCgp100. All these analyses will be described outside of this SAP and reported either in the Clinical Study Report 
or a stand-alone report. 
16.1.3. MISSING DATA METHODS FOR PHARMACOKINETIC DATA   
Missing PK concentration values will be reported as is in data listings, as ‘No Result’ or ‘No Sample’. Any missing 
PK parameter data will not be imputed. 
16.1.4. REPORTING OF PHARMACOKINETIC DATA 
For all PK data, descriptive statistics will follow the rounding convention described in Table B below. 
 
 
 
 
 
 
 
 


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Table B: 
Reporting Accuracy of Pharmacokinetic Data 
Variable / 
Parameter 
Listing 
Mean & 
Geometric 
mean 
Std & 
*HRPHWULF
PHDQ
JHRPHWULF
6WG 
%CV 
Median 
Min 
Max 
Plasma 
concentrations 
As reported 
+1sf 
+1sf 
1dp 
+1sf 
3sf 
3sf 
Single dose parameters 
AUClast  
3sf 
4sf 
4sf 
1dp 
4sf 
3sf 
3sf 
AUCinf 
3sf 
4sf 
4sf 
1dp 
4sf 
3sf 
3sf 
AUCtau 
3sf 
4sf 
4sf 
1dp 
4sf 
3sf 
3sf 
Cmax   
As reported 
+1sf 
 
+1sf 
 
1dp 
 
+1sf 
 
3sf 
 
3sf 
 
Tmax 
As reported 
NA 
NA 
NA 
 As 
reported  
 As 
reporte
d 
 As 
reported 
T1/2 
3sf 
NA 
NA 
NA 
4sf 
3sf 
3sf 
CL 
3sf 
4sf 
4sf 
1dp 
4sf 
3sf 
3sf 
CLSS 
3sf 
4sf 
4sf 
1dp 
4sf 
3sf 
3sf 
Vz 
3sf 
4sf 
4sf 
1dp 
4sf 
3sf 
3sf 
sf= significant figures; dp = decimal places; NA = Not Applicable 
“As reported” means that the plasma concentrations or parameters will be reported to the same precision as the 
source data. 


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17. IMMUNOGENICITY 
Blood samples for the evaluation of the development of immunogenicity responses are drawn at many visits’ pre-
dose as well as at the end of treatment visit. See Table 7-7 in the Protocol, Section 7.3.8 for the schedule of 
immunogenicity assessments. 
Anti-drug Antibody (ADA) analysis will be used to evaluate immunogenicity responses.  
17.1.1. ADA VARIABLES & DERIVATIONS 
Sample ADA values at each visit and time-point will be collected in the following formats, from a third-party vendor: 
x
Binding ADA result 
o
Positive: Final result in sample results spreadsheet (SRS) is Positive 
o
Negative: Final result in SRS is Negative and PK value is < drug tolerance limit of assay (200 ng/mL, 
which is equivalent to 200,000 pg/mL) 
o
Inconclusive: Final result in SRS is Negative and PK value is ≥ drug tolerance limit of assay (200 
ng/mL, which is equivalent to 200,000 pg/mL) or unknown  
o
Unevaluable: Sample was unable to be analyzed (insufficient volume, wrong matrix, etc.) 
x
Binding ADA Titer value 
x
Neutralizing ADA (NAb) result 
x
Neutralizing ADA titer value 
The following table gives the variables that will be derived for the binding ADA results and titers.  
Variable 
Definition 
Baseline ADA result & Baseline 
ADA titer 
See Section 6.2 
Pre-existing ADA 
Subject with Positive baseline ADA result (without a boost in titer in 
response to study drug administration). See below for definition of  
Treatment-boosted (≥4-fold) ADA. 
ADA prevalence at Baseline 
The number of subjects with a Positive ADA result at baseline as a 


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STATISTICAL ANALYSIS PLAN: 
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percentage of the total number of subjects tested at baseline for ADA. 
ADA Evaluable Subset 
All subjects who received at least one dose of study drug and have at 
least one ADA assessment post-baseline. This subset of the SAF will 
be used for determining ADA incidence. 
Max titer 
Highest titer value post-baseline. 
Peak (or max) fold increase in 
titer 
Ratio of max post-baseline titer to baseline titer (calculated only for 
subjects with a Positive ADA result at baseline). 
Treatment-induced ADA 
Subject in the ADA Evaluable Subset who has a positive ADA sample 
post-baseline with a Negative ADA result at baseline. 
Treatment-induced ADA 
Incidence 
Number of treatment-induced ADA subjects / Number of subjects in 
ADA Evaluable Subset with a Negative ADA result at baseline. 
 
Treatment-boosted (≥4-fold) 
ADA 
 
Subject in the ADA Evaluable Subset who has a Positive ADA sample 
at baseline and a Positive ADA sample post-baseline with a titer that 
has a peak (or max) fold increase in titer ≥4 compared to baseline. 
Treatment-boosted 
(≥4-fold) 
ADA incidence 
Number of treatment-boosted (≥4-fold) ADA subjects / Number of 
subjects in ADA Evaluable Subset with a Positive ADA result at 
baseline. 
Overall ADA Incidence (ADA 
Positive Subjects) 
All subjects with a treatment-induced or treatment-boosted ADA 
response (see definitions above) or subjects with positive post-
baseline ADA sample but do not have a baseline ADA sample in the 
ADA Evaluable Subset. 
ADA Negative Subjects 
All subjects without a treatment-induced nor treatment-boosted ADA 
response in the ADA Evaluable Subset (can include subjects classified 
as Pre-existing ADA). 
ADA Status 
Three categories:  
a. Unevaluable: Patient has no post-baseline ADA samples. 


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b. Positive: See “ADA Incidence (ADA Positive Subjects)” 
definition above. 
c.
Negative: See “ADA Negative Subjects” definition above (can 
include subjects classified as Pre-existing ADA). 
ADA Onset (as applicable) 
For subjects with a treatment-induced ADA response: number of days 
from first dose of study drug to the first instance of Positive ADA. 
Therefore, ADA Onset = (date of first instance of Positive ADA – date 
of first dose of study drug + 1). 
ADA Duration (as applicable) 
For subjects with a treatment-induced ADA response: number of days 
from the first instance of Positive ADA to last instance of Positive ADA 
for a subject, such that a subsequent Negative ADA follows the last 
instance of Positive ADA. 
Therefore, ADA Duration = (date of last Positive ADA* – date of first 
instance of Positive ADA + 1). 
*The last Positive has to exist such that a Negative ADA follows the 
last instance of Positive ADA. If the date of last Positive ADA result is 
the final ADA assessment, then ADA duration will be calculated 
above, but in this case, the duration will be concatenated with '+' to 
imply that the ADA duration is at least the calculated number of days. 
Transient ADA response  
ADA Positive subject (post-baseline) with at least one subsequent 
Negative result, after the last Positive result and the ADA Duration is 
< 20 weeks (i.e. < 140 days). 
Persistent ADA response 
Subject with either (i) an ADA Duration ≥ 20 weeks (i.e. ≥ 140 days), 
regardless of whether intervening sample results are Positive or 
Negative; or, (ii) if last sample is ADA Positive (i.e. where ADA 
Duration is concatenated with ‘+’as described above). 
 
 
 
 
 
 
 


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The following table gives the variables that will be derived for the neutralizing ADA results and titers. 
Variable 
Definition 
Neutralizing ADA status 
x
Positive: All binding ADA positive subjects with at least one 
positive neutralizing ADA result. 
x
Negative: All binding ADA positive subjects with a negative 
result for neutralizing ADA.  
Neutralizing ADA max titer 
Maximum value of the neutralizing ADA titer per subject. 
Overall neutralizing ADA 
incidence  
Number of positive neutralizing ADA subjects / Number of positive 
binding ADA subjects 
 
17.1.2. MISSING DATA METHODS FOR ADA 
Missing ADA values will be reported as is in data listings, as ‘No Result’ or ‘No Sample’. 
17.1.3. ANALYSIS OF ADA 
The ADA analysis comprises two parts; the ADA status summary at patient-level and the study ADA summary. The 
SAF will be used for all ADA summaries and listings. Details are summarized below: 
Patient ADA Status 
For each patient, the final ADA status (that considers the cumulative ADA sample results for that patient) will be 
summarized. This will include: 
x
ADA status (Unevaluable, Positive, Negative) 
x
ADA Characterisation (Treatment-induced, Treatment-boosted, or Pre-existing ADA) 
x
Time to ADA Onset for treatment-induced ADA patients 
x
ADA Duration category (Transient ADA response or Persistent ADA response) 


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x
Max titer for treatment-induced ADA patients 
x
Peak fold increase in titer for treatment-boosted ADA patients 
x
Neutralizing ADA status (Positive, Negative) 
x
Neutralizing ADA max titer 
Study ADA Summary 
At a study level, the ADA data summaries will include:  
x
The number (%) of patients who are ADA-positive at baseline – see ADA prevalence at Baseline 
definition above. 
x
The number (%) of evaluable patients – see ADA Evaluable Subset definition above. 
x
The number (%) of patients who are ADA-positive at follow-up – see Overall ADA incidence definition 
above. 
x
The number (%) of patients who are NAb positive at follow-up  - see Overall NAb incidence definition 
above.  
x
The number (%) patients with a treatment-induced ADA (from baseline negative) – see Treatment-
induced ADA incidence definition above. 
x
The number (%) patients with a treatment-boosted (≥4-fold) (from baseline positive) - see Treatment-
boosted (≥4-fold) ADA incidence definition above. 
x
The max titer from patients with treatment-induced ADA. Descriptive statistics including the median, 
IQR of the max titer will also be shown.  
x
The peak fold increase in titer among patients with treatment-boosted (≥4-fold) ADA. Descriptive 
statistics including the median, IQR of peak titer fold increases will also be shown. 
x
A graphical representation of time to ADA onset and ADA duration for patients with treatment-
induced ADA. Descriptive statistics (median, minimum and maximum) may also be summarized for 
time to ADA onset and ADA duration. 


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For all patients, all Sample ADA values (including regular ADA results and NAb results) collected at baseline and 
post-baseline will be listed. 
18. EXPLORATORY OBJECTIVES 
 
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18.3.
 
 
 
 
 
 
 
 
 
 
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18.4.
 
 
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
 
   
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. 
 
 
 
 
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19. DATA NOT SUMMARIZED OR PRESENTED 
The other variables and/or domains not summarized or presented are: 
x
Whole blood for DNA HLA typing (central) 
x
Disease Progression Follow Up and Safety Follow Up eCRF pages 
x
Collection of tumor sample in the setting of PD eCRF page 
x
Free text comments for any domains that are not listed specifically in the Listing Output Templates 
These domains and/or variables will not be summarized or presented, but will be available in the clinical study 
database, SDTM and/or ADaM datasets. Also note that the eCRF pages pertaining to 
 
exploratory endpoints will be covered outside of this SAP and output templates. 


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STATISTICAL ANALYSIS PLAN: 
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20. REFERENCES  
Brookmeyer, R., & Crowley, J. (1982). A Confidence Interval for the Median Survival Time. International Biometric 
Society, 38, 29-41. 
Clopper, C. J., & Pearson, E. S. (1934). The use of confidence or fiducial limits illustrated in the case of the binomial. 
Biometrika, 26, 404–413. 
EORTC 
Quality 
of 
Life 
Group. 
(2001). 
EORTC-QLC-C30 
scoring 
manual. 
Retrieved 
from 
EORTC: 
https://qol.eortc.org/manuals/ 
Kalbfleisch, J. D., & Prentice, R. L. (1980). The Statistical Analysis of Failure Time Data (First ed.). John Wiley & Sons, 
Inc. 
Lee, D. W. (2019). ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with 
Immune Effector Cells. Biology of Blood and Marrow Transplantation, 25, 625-638. 
 
 
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STATISTICAL ANALYSIS PLAN: 
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APPENDIX 1.
PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA OUTPUT CONVENTIONS 
Outputs will be presented according to the following IQVIA output conventions.  
 
1. ABBREVIATIONS 
 
x
ASCII  
American standard code for information interchange file format 
x
CGM  
Computer graphics metafile 
x
ODS  
Output Delivery System 
x
RTF  Rich text file format 
 
2. INTRODUCTION 
 
This document applies to standards used for outputting tables, listings and figures. It is intended to provide 
specifications to guide the statistician or statistical programmer in setting up specifications for programming tables, 
listings and figures. These standards should be used in the absence of customer specific standards. 
 
3. OUTPUT FILE NAMING CONVENTIONS 
 
File names should only consist of lowercase letters, digits (0 to 9) and underscores. A period should only be used to 
indicate a separator between the file name and the extension. No spaces, other special characters or punctuation 
marks are permitted. 
 
Output files should be in RTF format. 
 
The program, program log and output file name should reflect the type and number of the statistical output. If this 
is not possible, then the output name should be at least as descriptive as possible. A prefix can be used to 
distinguish between a Table, Listing and Figure document (‘t’ for table, ‘l’ for listing and ‘f’ for figure). If there is only 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
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1 digit in the number of the table, listing or figure in the place where 2 digits are possible, a leading zero should be 
added in the file name to make sorting consistent with the sequence (e.g. T14_3_01_1.RTF) 
 
4. PAPER SIZE, ORIENTATION AND MARGINS 
 
x
The size of paper will be A4. 
x
The page orientation should preferably be landscape, but portrait is also permitted. 
x
Margins should provide at least 3 centimeters of white space all around the page, regardless of the 
paper size. 
x
The number of columns per page (line size) should be 132 for A4. 
x
The number of rows per page (page size) should be 46 for A4. 
5. FONTS 
 
The font type ‘Courier New’ should be used as a default for tables and listings, with a font size of 8. The font color 
should be black. No bolding, underlining italics or subscripting should be permitted. Try to avoid using super-
scripts, unless absolutely necessary. Single spacing should be used for all text. 
Figures should have a default font of “Times Roman”, “Arial”, or “Courier New”. 
This can be achieved by using the following options in SAS for figures created using SG Procedures or GTL: 
 
proc template; 
 define style newfont; 
 parent = styles.rtf; 
 style GraphFonts from GraphFonts / 
 'GraphDataFont' = ("Courier New", 10pt) 
 'GraphLabelFont' = ("Courier New", 10pt) 
 'GraphValueFont' = ("Courier New", 10pt) 
 'GraphFootnoteFont' = ("Courier New", 10pt); 
 end; 
run; 
ods rtf style=newfont; 
 
6. HEADER INFORMATION 
 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
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Headers should be defined as follows: 
x
The header should be placed at the top of the page (same place on each page) regardless of the size 
or orientation of the table or listing. 
x
The sponsor name and Protocol number should appear in rows 1 and 2, left-aligned. 
x
The output identification number should appear in row 4, centered after a blank line in row 3. 
x
The output title should start in row 5, centered. 
x
The output population should appear in row 6, centered. The population should be spelled out in full, 
e.g. Full Analysis Set in preference to FAS. 
x
Row 7 should be a blank line. 
x
Row 8 should be a continuous row of underscores (‘_’) (the number of underscores should equal the 
line size). 
x
Sentence case should be used for titles. 
x
The output titles should be designed so that they are arranged consistently through all outputs. For 
example, content (e.g. Vital signs) followed by metric (e.g. change from baseline) e.g. Vital signs – 
change from baseline. 
x
Titles should not contain quotation marks or footnote references. 
x
The column headings should be underlined with a row of underscores (‘_’). 
x
Column headings spanning more than one column should be underlined and have underscores on 
either side of the title and should be centered. 
x
Column headings containing numbers should be centered. 
x
Column headings should be in proper case or sentence case. 
x
In general, the population count should appear in the column header in the form “(N=XXX)”. 
x
“Statistic” should be the column header over n, Mean, SE, n (%) etc. 


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STATISTICAL ANALYSIS PLAN: 
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Page 100 of 131
x
As a rule, all columns should have column headings if possible. 
 
7. TABLE AND LISTING OUTPUT CONVENTIONS 
 
General: 
x
The first row in the body of the table or listing should be blank. 
x
The left-hand column should start in column 1. No indenting or centering of the output should occur. 
x
Rounding should be done with the SAS function ROUND. 
x
Numbers in tables should be rounded, not truncated. 
x
Alphanumeric output should be left aligned. 
x
Numbers should be decimal point aligned, where possible. 
x
Whole numbers should be right aligned. 
x
Text values should be left aligned. 
x
The first letter of a text entry should be capitalized. 
x
Listings of adverse events, concomitant medications, medical histories etc. should be sorted in 
chronological order, with earliest adverse event, medication or history coming first. 
x
The study drug should appear first in tables with treatments as columns. 
x
All listing outputs should be sorted (preferably by Treatment, Patient Identifier [Site Number + Patient 
Number]). 
x
Do not use superscripts and subscripts. 
x
Exponentiation will be expressed without superscripts, i.e., m2 will be displayed as m2. 
x
The width of the entire output should match the line size. 


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STATISTICAL ANALYSIS PLAN: 
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Univariate Statistics: 
 
x
Statistics should be presented in the same order across tables (i.e., n, Mean, Std, Median, Minimum, 
Maximum). 
x
Table statistics should line up under the N part of the (N=XXX) in the table header. All decimal points 
should line up. If the minimum and maximum are output on one line as Minimum, Maximum then 
the comma should line up with the decimal point. 
x
If the original data has N decimal places, then the summary statistics should have the following 
decimal places: 
o
Minimum and maximum: N, 
o
Mean, median and CV%: N + 1, 
o
Std: N + 2. 
Note: An exception to this rule is for demography and other baseline characteristics summaries, in which the 
precision of the original data can be ignored, if fewer decimal places suit the statistical summary better. The full 
decimal precision (places) will be shown in Listings in these cases. 
Frequencies and percentages (n and %): 
 
x
Percent values should be reported inside parentheses, with one space between the count and the 
left parenthesis of the percentage. Parentheses should be justified to accept a maximum of 100.0 as 
a value and padded with blank space if the percent is less than 100.0. An example is given below: 
 77 (100.0%) 
50 ( 64.9%) 
                                                                                                0 (   0.0%) 
x
Percentages will be reported to one decimal place, except percents <100.0% but >99.9% will be 
presented as ‘>99.9%’ (e.g., 99.99% is presented as >99.9%); and percents < 0.1% will be presented 
as ‘<0.1%’ (e.g., 0.08% is presented as <0.1%). Rounding will be applied after the <0.1% and >99.9% 
rule. For example: 
 ( <0.1%) 


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STATISTICAL ANALYSIS PLAN: 
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Page 102 of 131
( 6.8%) 
(>99.9%) 
x
Percentages may be reported to 0 decimal places as appropriate (for example, where the 
denominator is relatively small). 
x
Where counts are zero, percentages will not appear in the output. 
 
Confidence Intervals: 
 
x
As a rule, confidence intervals are output to one place more than the raw data, and standard 
deviations and standard errors to two places more than the raw data. 
x
Confidence intervals should be justified so that parentheses displayed on consecutive lines of a table 
“line up”. However, parentheses do not have to be used. 
x
Boundary values of confidence intervals should be separated by a comma. 
x
Boundary values should be padded as necessary to accept negative values and to allow alignment of 
the decimal place. 
x
An example is given below: 
 -0.12,  -0.10 
  9.54, 12.91 
 
Ratios: 
 
x
Ratios should be reported to one more decimal place than the original data. 
 
Spacing: 
 
x
There must be a minimum of 1 blank space between columns (preferably 2). 
Denominators: 


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x
If a different count other than the population count is used for a denominator (within the table) to 
calculate percentages, there should be a row in the table that identifies that number “n”. 
x
Alternatively, a footnote should be included in each table with percentages to indicate the 
denominator for percentages. 
 
Missing values: 
 
x
A “0” should be used to indicate a zero frequency. 
x
A blank or ‘-‘ will be used to indicate missing data in an end-of-text table or patient listing. 
x
In the case that only a single value is used in the creation of summary statistics (i.e. n=1) then only n, 
mean, median, minimum and maximum will be presented. 
 
8. FIGURE OUTPUT CONVENTIONS 
 
x
Figures should be provided in RTF files using the SAS Output Delivery System (ODS). Formats such as 
Computer Graphics Metafile (CGM), PNG (Portable Network Graphic), etc. should be used for the 
formatted graphical output generated by SAS. 
x
The CGM/PNG/etc. graphical file itself may or may not contain the title or footer. 
x
The image should be clear and of high quality when viewed in the Word document, and when printed. 
x
In general, boxes around the figures should be used. 
 
9. FOOTNOTE INFORMATION 
 
Footers should be defined as follows: 
x
A continuous line of underscores (‘_’) will follow the body of the table or listing prior to any footnotes 
at the bottom of the page. 
x
Table footnotes should be defined using compute statements in the proc report and should appear 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
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directly after the body of the table. 
x
The program path and name and version number (if applicable) should appear as the last footnote at 
the bottom of the page. 
x
The date/time stamp should appear directly after the program path and name. 
x
Footnotes should be left-aligned. 
x
Footnotes should be in sentence case. 
x
Only “typewriter” symbols should be used where possible – e.g. “*”, “$”, “#”, “@”, “&” and “+”. 
However, other symbols may be added as required.  
x
The choice of footnote symbols should be consistent. E.g. if you have the footnote “# indicates last 
observation carried forward” for one table, the same symbol and footnote should indicate LOCF for 
all tables. 
x
If text wraps across more than one line (for a note), the first letter for all lines of text after the first 
one will be indented to align beneath the first letter of the text in the first line (if possible). 
x
The page identification in the format Page X of Y (where Y is the total number of pages for the output) 
will appear at the bottom of the page, right aligned. 
 
Ordering of footnotes should be as follows: 
 
1.) Abbreviations and definitions 
2.) Formulae 
3.) Symbols 
4.) Specific notes 
5.) Source data listing reference, if necessary 
 
x
Common notes from table to table should appear in the same order. 


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x
The symbols should appear in the same order as what they are defined in the table or listing, from 
left to right. 
 
10. PROGRAMMING INSTRUCTIONS 
 
Programming instructions must appear in blue font at the end of each table or listing shell. Programming 
instructions, where necessary, should follow the table or listing shells in blue font, beginning with the words 
“Programming Note” followed by a colon. These include notes on the output, reminders of how to handle missing 
values, repeat shells for similar tables etc. 
DATES & TIMES 
Depending on data available, dates and times will take the form DDMMMYYYY HH:MM. 
SPELLING FORMAT 
English US 
PRESENTATION OF TREATMENT GROUPS 
EFFICACY 
 
For all primary and secondary efficacy Tables and most Figures, treatment groups will be represented differently 
for each Phase of the study. For listings, each cohort of patients will be listed separately. 
For Phase 1 dose escalation cohorts: Patients will be pooled into a total treatment group  
Treatment Group 
For Tables and Figures 
For Listings 
IMCgp100 xx mcg 
Phase 1 dose escalation cohorts - 
Total 
Cohort x: IMCgp100 xx mcg 
For the Phase 1 dose escalation cohorts, some efficacy figures will additionally be presented by IMCgp100 dose 
level.  
For Phase 2 dose expansion cohort: Patients presented by a single treatment arm, presented as follows. There is 


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STATISTICAL ANALYSIS PLAN: 
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a single dose, which will be known before this cohort of patients is assigned to treatment.   
Treatment Group 
For Tables and Figures 
For Listings 
IMCgp100 xx mcg 
Expansion:  IMCgp100 xx mcg 
Cohort x: IMCgp100 xx mcg 
 
For the Phase 2 dose expansion cohort, some efficacy tables and figures will be presented by subgroup, as per 
Section 7.5.  
NON-EFFICACY 
For all other Tables and Figures (including Study Population, Exposure, and Safety) treatment groups will be 
represented differently for each Phase of the study, as follows: 
For Phase 1 dose escalation cohorts: Patients treated with the same dose will be pooled into treatment ‘groups’, 
defined by a unique set of doses. ‘Groups’ will be presented as follows from minimum to maximum protocol-
assigned dose level (at C1D15).  
Treatment Group 
For Tables and Figures 
For Listings 
IMCgp100 xx mcg 
Phase 1 dose escalation cohorts: 
IMCgp100 xx mcg 
Cohort x: IMCgp100 xx mcg 
 
For Phase 2 dose expansion cohort: Patients presented by a single treatment arm, presented as follows. There is 
a single dose, which will be known before this cohort of patients is assigned to treatment.   
Treatment Group 
For Tables and Figures 
For Listings 
IMCgp100 xx mcg 
Expansion: IMCgp100 xx mcg 
Cohort x: IMCgp100 xx mcg 
 
For Screen Failures and Not Assigned:  
Treatment Group 
For Tables and Figures 
For Listings 
Not Assigned 
-  
Not Assigned 
Screen Failure 
- 
Screen Failures 
 


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STATISTICAL ANALYSIS PLAN: 
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PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Screening 
Scr 
Baseline 
BL 
Treatment Period 
Cycle 1 Day 1 
C1D1 
Cycle 1 Day 2 
C1D2 
Cycle 1 Day 8 
C1D8 
Cycle 1 Day 15 
C1D15 
Cycle 1 Day 16 
C1D16 
Cycle 1 Day 22 
C1D22 
Cycle 2 Day 1 
C2D1 
… 
… 
End of Treatment record 
End of Treatment 
EoT 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 


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x
Phase (Phase 1 dose escalation cohorts, followed by Expansion cohort) 
x
Phase 1 dose escalation cohorts should be presented in ascending dose order,  
x
Center-patient ID,  
x
Visit (where applicable) 
x
Date and time (where applicable), 
x
For listings where Screen Failures are included, these will appear in a category after the 
randomized/actual treatment groups labelled as ‘Screen Failures’. 
 
 
 
 
 
 
 
 
 
 
 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 109 of 131
APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
Note: The start date of subsequent alternative cancer therapy will only be considered below, if the start date of 
alternative cancer therapy is greater than the study drug end date*. The start date of subsequent alternative 
cancer therapy is derived as the earliest start date from (i) alternative cancer therapies entered on the Prior and 
Concomitant Medications eCRF page (see Section 12.1) which occur after the date of last dose of study drug, and 
(ii) from therapies entered on the Antineoplastic therapies since discontinuation eCRF page (see Section 12.2). 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If start date < study drug start date, then not TEAE 
If start date ≥ study drug start date and start date ≤ 
Minimum[study drug end date + 90, start date of 
subsequent alternative cancer therapy*], then TEAE 
If start date > Minimum[study drug end date + 90, start date 
of subsequent alternative cancer therapy*], then not TEAE 
Note: If study drug end date is missing, then as long as start 
date ≥ study drug start date, then TEAE 
 
Partial 
If start date < study drug start date, then not TEAE 
If start date ≥ study drug start date and start date ≤ 
Minimum[study drug end date + 90, start date of 
subsequent alternative cancer therapy*], then TEAE 
If start date > Minimum[study drug end date + 90, start date 
of subsequent alternative cancer therapy*], then not TEAE 
Note: If study drug end date is missing, then as long as start 
date ≥ study drug start date, then TEAE 
 
Missing 
If start date < study drug start date, then not TEAE 
If start date ≥ study drug start date and start date ≤ 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 110 of 131
START DATE 
STOP DATE 
ACTION 
Minimum[study drug end date + 90, start date of 
subsequent alternative cancer therapy*], then TEAE 
If start date > Minimum[study drug end date + 90, start date 
of subsequent alternative cancer therapy*], then not TEAE 
Note: If study drug end date is missing, then as long as start 
date ≥ study drug start date, then TEAE 
 
 
 
Partial, but known 
components (month/year 
or year) show that start 
date cannot be on or after 
study drug start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or after 
study drug start date (i.e. 
same month/year or after, 
or year after) 
Known 
If stop date < study drug start date, then not TEAE 
If stop date ≥ study drug start date, then impute start date 
as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown). 
Then, consider the following: 
-If start date ≤ Minimum[study drug end date + 90, start date 
of subsequent alternative cancer therapy*], then TEAE 
-If start date > Minimum[study drug end date + 90, start date 
of subsequent alternative cancer therapy*], then not TEAE 
Note: If study drug end date is missing, then as long as start 
is same month/year or same year as study drug start date, 
then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 111 of 131
START DATE 
STOP DATE 
ACTION 
are unknown), then: 
If stop date < study drug start date, then not TEAE 
If stop date ≥ study drug start date, then impute start date 
as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown). 
Then, consider the following: 
-If start date ≤ Minimum[study drug end date + 90, start date 
of subsequent alternative cancer therapy*], then TEAE 
-If start date > Minimum[study drug end date + 90, start date 
of subsequent alternative cancer therapy*], then not TEAE 
Note: If study drug end date is missing, then as long as start 
is same month/year or same year as study drug start date, 
then TEAE 
 
Missing 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown). Then, consider the following: 
-If start date ≤ Minimum[study drug end date + 90, start date 
of subsequent alternative cancer therapy*], then TEAE 
-If start date > Minimum[study drug end date + 90, start date 
of subsequent alternative cancer therapy*], then not TEAE 
Note: If study drug end date is missing, then as long as start 
is same month/year or same year as study drug start date, 
then TEAE 
 
 
 
Missing 
Known 
If stop date < study drug start date, then not TEAE 
If stop date ≥ study drug start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 112 of 131
START DATE 
STOP DATE 
ACTION 
If stop date < study drug start date, then not TEAE 
If stop date ≥ study drug start date, then TEAE 
 
Missing 
Assumed TEAE 

ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study drug start date, assign as prior  
If stop date ≥ study drug start date and start date ≤ end of treatment, 
assign as concomitant  
If stop date ≥ study drug start date and start date > end of treatment, 
assign as post treatment 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study drug start date, assign as prior 
If stop date ≥ study drug start date and start date ≤ end of treatment, 
assign as concomitant 
If stop date ≥ study drug start date and start date > end of treatment, 
assign as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date ≤ end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date < study drug start date, assign as prior 
If stop date ≥ study drug start date and start date ≤ end of treatment, 
assign as concomitant 
If stop date ≥ study drug start date and start date > end of treatment, 
assign as post treatment 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 113 of 131
START DATE 
STOP DATE 
ACTION 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute stop 
date as latest possible date (i.e. last day of month if day unknown or 31st 
December if day and month are unknown), then: 
If stop date < study drug start date, assign as prior 
If stop date ≥ study drug start date and start date ≤ end of treatment, 
assign as concomitant 
If stop date ≥ study drug start date and start date > end of treatment, 
assign as post treatment 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date ≤ end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < study drug start date, assign as prior 
If stop date ≥ study drug start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study drug start date, assign as prior 
If stop date ≥ study drug start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 
 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 114 of 131
ALGORITHM FOR ANTI-NEOPLASTIC THERAPIES POST TREATMENT DISCONTINUATION:  
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study drug start date, assign as prior 
If stop date ≥ study drug start date and start date ≤ end of treatment, assign 
as concomitant,   
If stop date ≥ study drug start date and start date > end of treatment, assign 
as post treatment  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study drug start date, assign as prior 
If stop date ≥ study drug start date and start date ≤ end of treatment, assign 
as concomitant 
If stop date ≥ study drug start date and start date > end of treatment, assign 
as post treatment 
 
Missing 
If start date ≤ end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Partial 
Known 
Impute start date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown, provided the 
stop date is not before the imputed start date (if so set to: stop date)), 
then: 
If stop date < study drug start date, assign as prior 
If stop date ≥ study drug start date and start date ≤ end of treatment, assign 
as concomitant 
If stop date ≥ study drug start date and start date > end of treatment, assign 
as post treatment 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 115 of 131
START DATE 
STOP DATE 
ACTION 
 
Partial 
Impute start date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown, provided the 
imputed stop date is not before the imputed start date (if so set to: 
imputed stop date))  
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: If stop 
date < study drug start date, assign as prior 
If stop date ≥ study drug start date and start date ≤ end of treatment, assign 
as concomitant 
If stop date ≥ study drug start date and start date > end of treatment, assign 
as post treatment 
 
Missing 
Impute start date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If start date ≤ end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
Impute start date as stop date, then: 
If stop date < study drug start date, assign as prior 
If stop date  study drug start date and start date ൑ end of treatment, 
assign as concomitant 
If stop date  study drug start date and start date > end of treatment, 
assign as post treatment 
 
Partial 
Impute start date as stop date 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study drug start date, assign as prior 
If stop date ≥ study drug start date and start date ≤ end of treatment, assign 
as concomitant 
If stop date ≥ study drug start date and start date > end of treatment, assign 
as post treatment 
 
Missing 
Impute start date as “study drug end date + 91”. 
Assign as post treatment. 
Cannot be assigned as ‘prior’ or ‘concomitant’ 


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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 116 of 131
 
  
 
  
 
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Page 117 of 131
 
APPENDIX 5.
DATA CUT-OFF APPROACH FOR SDTM DATA  
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STATISTICAL ANALYSIS PLAN: 
PROTOCOL IMCgp100-102 
Page 130 of 131
APPENDIX 6.
PROCESS FOR CATEGORIZING SKIN TOXICITIES ASSOCIATED WITH 
TEBENTAFUSP, INCLUDING RASH 
Since gp100 is expressed on melanocytes on the skin, tebentafusp was expected to induce a skin rash and indeed 
this was observed.  These adverse events may present in different ways and be reported by investigators using 
different AE preferred terms (PTs). Therefore, for the purpose of detailed safety evaluations, Immunocore 
designed a process to determine a composite list of rash:  
1. All unique MedDRA PTs under the System Organ Class (SOC) of “Skin and subcutaneous tissue disorders” 
from study IMCgp100-102 were listed and reviewed by the study’s medical monitor.   
2. PTs were then grouped into only one of several skin toxicity composite terms based this medical review: 
a. Rash 
b. Pruritis 
c.
Pigment change 
d. Erythema 
e. Edema  
f.
Dry skin 
g.
Other changes 
3. Due to their suspected relationship to the tebentafusp mechanism of action, the following PTs from other 
SOCs were also added to these categories: 
a. Eye pruritus (to Pruritis) 
b. Eyelash hypopigmentation (to Pigment change) 
c.
Periorbital oedema (to Edema) 
4. The process was repeated for the first-in-human study IMCgp100-01, which included some new PTs in the 
Skin and subcutaneous tissue disorders SOC that were not reported in study IMCgp100-102 and a few PTs 
from other SOCs (Eyelash discolouration, Erythema of the eyelid, Skin abrasion, Eyelid eodema).  All  of 
these PTs were added to the relevant composite lists. 
5. The composite lists were reviewed by oncologists who were high volume enrollers on the tebentafusp 
clinical trials. Based on their input, only a few PTs were adjusted by from one composite list to another. 
6. The resulting list of rash PTs is: Blister, Dermatitis acneiform, Dermatitis allergic, Dermatitis bullous, 


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Dermatitis exfoliative, Drug eruption, Eczema, Palmar-plantar erythrodysaesthesia syndrome, Papule, 
Psoriasis, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash papular, 
Rash pruritic, Rash vesicular, Skin abrasion, Skin exfoliation, Urticaria.