PIWIL1 ISH ASSAY CLINICAL PERFORMANCE STUDY IN FFPE SPECIMENS FROM SUBJECTS WITH ADVANCED TUMORS FOR ENROLMENT WITHIN THE CLINICAL TRIAL IMC-R117C-1004

STUDY PURPOSE
The purpose of this study is to prospectively screen FFPE human tissue tumor
cell samples from study subjects with advanced colorectal, esophageal, gastric,
and ovarian cancers with the PIWIL1 ISH assay to establish patient eligibility
for the Immunocore clinical trial, *A Phase 1/2 First-in-Human Study of the
Safety and Efficacy of IMC-R117C (PIWIL1 × CD3 ImmTAC® Bispecific Protein) as a
Single Agent and in Combination in HLA-A*02:01-Positive Participants with
Selected Advanced PIWIL1-Positive Cancers*. For the evaluation of patient
specimens for the Immunocore Limited clinical study LoQ/cut-off was set at 10%
positivity by the Sponsor based on in-house data on PIWIL1 ISH expression and
peptide levels. It was determined that 10% is the lowest amount concentration
where the level of target peptide fragment of PIWIL1 presented by HLA-A*02:01
can be identified. A result of >=% 10 is considered positive for PIWIL1
expression, and a result of <10% is considered negative.

The purpose of this study is to evaluate the clinical utility of the PIWIL1 ISH
assay as a CDx, as well as screening for inclusion in the Immunocore clinical
study.

ASSAY UNDER EVALUATION
NeoGenomics PIWIL1 ISH Clinical Trial Assay

INCLUSION CRITERIA FOR IMC-R117C-004
1. Participant must be >=18 years of age, inclusive, at the time of signing the
ICF
2. ECOG status of 0 or 1 at start of treatment
3. HLA-A*02:01-positive (testing at central laboratory).
4. PIWIL1 expression in >=10% of tumor cells must be established in patient
specimen.
5. Histologically confirmed advanced (i.e., either locally advanced or
metastatic disease that is unresectable) colorectal, esophageal, gastric, or
ovarian carcinoma.
6. Participants must meet tumor PIWIL1 testing requirements:
a. ALL COHORTS: An archival or newly collected tumor biopsy must be sent to the
study central laboratory. An archival biopsy may be provided as an FFPE tissue
block, or an FFPE pre-cut slide.
b. MONOTHERAPY COHORTS: a tumor biopsy sample must be sent to the study central
laboratory and a positive result must be received prior to enrolling. If data
indicate that clinical activity is restricted to participants with higher tumor
PIWIL1 expression, subsequent enrollment may be restricted to participants
whose tumors are confirmed as having higher PIWIL1 expression; details will be
documented in the SPM.
c. COMBINATION COHORTS: An archival or newly collected tumor biopsy must be
confirmed as adequate (as defined in the study Laboratory Manual) locally prior
to completion of Screening and subsequently sent to the study central
laboratory. If data indicate that clinical activity is restricted to
participants with higher tumor PIWIL1 expression, subsequent enrollment may be
restricted to participants whose tumors are confirmed as having higher PIWIL1
expression; details will be documented in the SPM.
7. Participants must meet RECIST v1.1 criteria for evaluable/measurable disease
based on investigator assessment:
a. In dose-escalation, regimen optimization, and Phase 2, participants must
have evaluable disease (at least 1 non-target or target lesion),
b. In expansion, all participants must have at least 1 target lesion.
c. Tumors in irradiated areas are acceptable only if there is subsequent
documented radiographic progression
8. Participants must meet the histology, biomarker, and prior treatment
requirements specified in Table 9 of the lmmunocore study protocol for the
applicable arm and study part. Required therapies must have been given for
unresectable/metastatic disease or in the neoadjuvant or adjuvant setting with
disease progression during or within 6 months of completing neoadjuvant or
adjuvant therapy.
9. Male and female participants of childbearing potential who are sexually
active with a non¬ sterilized partner must agree to use highly effective
methods of birth control from the study screening date until 6 months after the
final dose of the study treatment; cessation of birth control after this point
shall be discussed with a responsible physician. Highly effective methods of
contraception are described in Section 10.5 of the lmmunocore study protocol.
a. Pregnant or lactating women are prohibited from enrolling in this study.
b. Male participants are not allowed to donate sperm from the time of
enrollment until 6 months post-administration of study treatments.
10. Capable of giving signed informed consent as described in Section 10.1.3 of
the lmmunocore study protocol, which includes compliance with the requirements
and restrictions listed in the lmmunocore ICF and protocol.

EXCLUSION CRITERIA FOR IMC-R117C-004
1. Presence of untreated or symptomatic CNS metastases, leptomeningeal disease,
or cord compression. NOTE: Participants with treated CNS lesions may enroll
provided all the following apply:
a. Treated CNS lesions must be radiographically stable for >=2 weeks after
intervention (surgery and/or radiation).
b. Participants must be neurologically stable off systemic corticosteroids for
at least 2 weeks prior to enrollment.
2. Bowel obstruction within 3 months prior to the planned first dose of study
treatment
3. Participants at high risk for vital organ perforation, fistula formation, or
hemorrhage, defined as:
a. History of gastrointestinal perforation, abdominal fistula, intra-abdominal
abscess, or active gastrointestinal bleeding within 6 months of the first dose
of study treatment OR
b. Single tumor lesion with diameter > 100 mm, tumor adjacent to or directly
involving the surface of a vital organ (e.g., serosal surface of the bowel,
airway, or major vessel), AND treatment with an anti-angiogenic agent within 3
months of the first dose of study treatment
4. Ongoing ascites or effusion requiring recurrent drainage (i.e, at least
twice within 28 days prior to the planned first dose of study treatment). NOTE:
Participants with an indwelling catheter in place for at least 14 days prior to
the planned first dose of study treatment may be eligible following discussion
with the study medical monitor.
a. For combination with bevacizumab, any ascites or effusion requiring drainage
within 28 days prior to the first dose of study treatment is exclusionary
5. Participants with presence of NCI CTCAE >=Grade 2 toxicity due to prior
cancer therapy, with the following exceptions:
a. Participants with Grade 2 alopecia, Grade 2 endocrine disorder (on stable
replacement doses and asymptomatic), Grade 2 hypophosphatemia (on appropriate
replacement therapy), Grade 2 ototoxicity, or Grade 2 peripheral neuropathy may
enroll in any arm.
b. Participants with other stable Grade 2 toxicities due to prior anticancer
therapy, that are anticipated to have minimal risk of worsening due to
treatment with IMC-R117C and applicable combination partner(s), may enroll only
with prior written approval from the study medical monitor.
6. Hypersensitivity to:
a. IMC-R117C or any associated excipients (all arms),
b. Bevacizumab, Chinese Hamster Ovary cell products, other recombinant human or
humanized antibodies, 5-FU, capecitabine, or any associated excipients (Arm
Band Arm D)
c. Cetuximab, encorafenib, or any associated excipients (Arm C)
7. Receipt of anticancer therapy for the disease under study within the
following times prior to the first planned dose of study treatment (NOTE:
washout periods do not apply to therapies that will be continued as combination
partners. For maintenance arms, washout periods do not apply to therapies given
for induction):
a. Cellular therapies (e.g., T-cell therapies): 90 days. NOTE: The investigator
must discuss any prior cellular therapy treatment with the medical monitor,
provide evidence (if possible) confirming that no residual
biological/immunological activity remains, discuss any associated potential
risks, and determine whether any additional monitoring is indicated. In
additi

To evaluate the clinical utility of the PIWIL1 ISH assay for predicting
response of patients with Advanced PIWIL1-Positive Cancers within the
lmmunocore clinical study. To determine the role of PIWIL1 expression as a
potential predictor of efficacy based on the ORR for evaluable samples tested
using the PIWIL1 ISH assay

This is an interventional first-in-human study of the safety and efficacy of
IMC-R117C as a single agent and in combination with other therapeutic agents in
HLA-A*02:01-positive participants with advanced PIWIL1-positive cancers. This
study is designed to assess the safety, tolerability, PK, immunogenicity,
pharmacodynamics, and antitumor activity of IMC-R117C as a monotherapy and in
combination with other agents. This study is a minimally invasive surgical
procedure, containing prospective collection of tumor biopsy samples to test
for expression of PIWIL1.

N/A

1. SUMMARY OF RISKS
1. POTENTIAL RISKS OF THE CLINICAL PERFORMANCE STUDY

NeoGenomics Laboratories has assessed the potential patient risks associated
with the use of the PIWIL1 ISH assay for the detection of the PIWIL1 tumor cell
expression in FFPE specimens from patients with a diagnosis of advanced
colorectal, esophageal, gastric, and ovarian cancer as part of inclusion
criteria within the lmmunocore Limited clinical study. The PIWIL1 ISH assay
does not provide a primary disease diagnosis, it provides the PIWIL1 expression
status in patients previously diagnosed with advanced solid tumors.
Patients will be enrolled based on stringent inclusion/exclusion criteria and
those who are evaluated for entry into the study will be informed of the risks
of treatment with the investigational therapy that has not yet proven to
provide therapeutic benefit. The collection of a FFPE specimens is part of
routine clinical practice for evaluation of solid tumor malignancies and risks
associated with a FFPE specimen biopsy are defined in the patient informed
consent form. For this central laboratory testing of PIWIL1 expression status,
there are no direct patient risks. Therefore, patients who sign the informed
consent forms are considered by their physicians to be suitable for accepting
these risks. The controls put in place to monitor and conduct the study will
also help to ensure the safety, rights, and welfare of the subjects enrolled
into the trial.
Given the nature of this device study and the mitigation of identified risks,
the residual risk to patients whose sample specimen is tested is acceptable. A
failure mode and effect analysis were conducted to ensure that risks relating
to the design and use of the device use are as low as reasonably possible. A
risk management report will summarize the outcome of the risk assessment
including a risk-benefit assessment for patients participating in this device
study.

NeoGenomics has assessed the risks associated with the use of the PIWIL1 ISH
assay to be utilized within the lmmunocore clinical study IMC-R117C-1004 as
presented within this CPSP. NeoGenomics believes the potential benefits
outweigh patient risks based on the following criteria:
• Risks associated with device design and use have been reduced to be as low as
possible.

• The PIWIL1 ISH assay is not intended to provide a primary disease diagnosis,
it is intended to be used to confirm PIWIL1 expression status in patient
specimen with a confirmed diagnose of advanced solid tumors.
• The PIWIL1 ISH assay is being utilized as a CTA for the detection of the
PIWIL1 expression in FFPE tumor specimens. All specimen testing will be
performed solely at NeoGenomics Laboratories which are high-complexity CLIA
and/or CAP accredited facilities.
• The PIWIL1 ISH assay is NOT a near patient device, therefore, there are no
direct risks to patients or healthcare workers.
• The PIWIL1 ISH assay has been validated according to Clinical Laboratory
Standards Institute (CLSI) standards, and the validation testing satisfied all
the pre-defined acceptance criteria.
• The PIWIL1 ISH assay is NOT a packaged and distributed IVD kit, the assay is
performed at high complexity clinical laboratories which have validated the
assay for its intended purpose for the lmmunocore clinical study.
• Each PIWIL1 ISH assay result is reviewed and signed by a NeoGenomics
Laboratories board-certified pathologist.

2. RISK ASSOCIATED WITH BIOPSY PROCEDURES
For subjects who will be enrolled in the study, tumor material (FFPE block,
slides, or wet tissue) is requested at screening for confirmatory and biomarker
testing. Risk associated with a tumor biopsy are defined in the lmmunocore
protocol and ICF. Left-over specimen banks, genetic or tissue bank are not
applicable for this study. Therefore, no biorepositories requirements for this
study and all left-over specimens will be destroyed/ discarded at the end of
the study.
3. INVESTIGATIONAL THERAPY RELATED RISK
Risk associated to IMC-R117C-1004 are defined in lmmunocore clinical protocol
and investigators brochure.
4. RISKS ASSOCIATED WITH THE PIWIL1 ISH ASSAY
A Failure Modes and Effect Analysis (FMEA) has been conducted to ensure that
the risks associated with the PIWIL1 ISH assay related to the design and use of
the device use are as low as reasonably possible. Details of that FMEA will be
included in the final risk management report. Additionally, PIWIL1 ISH assay
risks and anticipated adverse device effects only includes false positive and
false negative test results provided to clinical study site.
5. POTENTIAL BENEFITS OF THE PIWIL1 ISH ASSAY
The objective of this study is to screen PIWIL1 expression by ISH in FFPE
patient specimens with a confirmed diagnosis of advanced solid tumors to
establish study eligibility for the lmmunocore clinical study. Given the
encouraging preliminary efficacy and the acceptable safety profile in IMC-R117C
the benefit/risk of IMC-R117C in patients with PIWIL1+ solid tumor warrants
continued investigation.