A Phase 1, Open-label, Dose-escalation and Expansion Study of MEDI1191 Administered Intratumorally as Monotherapy and in Combination with Durvalumab in Subjects with Advanced Solid
Tumors.
Sub-study title: CD8+ Imaging Sub-study Protocol

Please note that due to removing inclusion/ exclusion criteria not relevant for
the protocol conducted in The Netherlands, the numbers deviate from those in
the Main Protocol.

Subjects must meet all of the following criteria:
1. Subjects >= 18 years of age.
2. Have given written informed consent prior to any study prior to performing
any protocol related procedures, including screening evaluations.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
4. Have at least 1 measurable lesion, other than the planned injected
lesion(s), using standard techniques by RECIST v1.1. Injected tumor lesion(s)
must be deemed clinically feasible for injection by the investigator.
a. A previously irradiated lesion, or a lesion subjected to other loco-regional
therapy, can be considered a target lesion only if the lesion has clearly
progressed during or after most recent therapy, and is well defined, measurable
per RECIST v1.1.
b. Subjects undergoing fresh tumor biopsies must have additional non-target
lesions that can be biopsied at acceptable risk as judged by the investigator
or if no other lesion is deemed suitable for biopsy, then a RECIST v1.1 target
lesion used for biopsy must be >= 2 cm in longest diameter.
5. Adequate bone marrow, renal, and hepatic function
a. Hematological (criteria listed cannot be met with recent blood transfusions
or require ongoing growth factor support within 2 weeks of starting study
treatment):
i. Absolute neutrophil count >= 1.5 × 109/L (1,500/mm3).
ii. Platelet count >= 100 × 109/L (100,000/mm3).
iii. Hemoglobin >= 9.0 g/dL within first 2 weeks prior to first dose.
b. Renal: calculated creatinine clearance (CrCL) (Cockcroft-Gault formula will
be used to calculate CrCL) or 24-hour urine CrCl > 50 mL/min.
c. Hepatic:
i. TBL <= 1.5 × ULN; for subjects with documented/suspected Gilbert's syndrome
or liver metastases, bilirubin <= 3 × ULN.
ii. AST and ALT <= 3 × ULN if no demonstrable liver metastasis; <= 5 x ULN in the
presence of liver metastases.
iii. Albumin > 3 g/dL.
iv. International normalized ratio (INR) and activated partial thromboplastin
time (aPTT) < 1.5 × ULN.
6. Prior to the first dose of MEDI1191, subjects with central nervous system
(CNS) metastases must have been treated and must be asymptomatic and meet the
following:
a. No concurrent treatment, inclusive of but not limited to surgery, radiation,
and/or corticosteroids.
b. Subjects must be clinically stable with no CNS symptoms following CNS
treatment for a period of at least 28 days prior to first dose of MEDI1191.
c. At least 7 days since last dose of corticosteroids first dose of MEDI1191.
NOTE: Subjects with clinical symptoms or cord compression or with
leptomeningeal disease are excluded from the study.
7. Cessation of immunosuppressive medications including systemic
corticosteroids at doses exceeding 12 mg/day prednisone or equivalent,
methotrexate, azathioprine, ustekinumab (Stelara®), and tumor necrosis factor
(TNF) α/IL 6 blockers for at least 7 days prior to the first dose of MEDI1191
(corticosteroids at doses of 12 mg/day prednisone equivalent or lower, inhaled,
intranasal, intraarticular, and topical steroids are permitted).
8. The imaging and the results of imaging done up to 6 months prior to
screening (ie, >= 1 additional time point before baseline assessment) are to be
made available to the sponsor for evaluation of the kinetics of tumor
progression if allowed by country.
9. Subjects with cutaneous or subcutaneous tumor lesions are defined as visible
or palpable non-visceral lesions for Part 1A, 1B, and Part 2 expansion cohorts.
This definition includes lesions involving superficial muscle tissue and
lesions involving the fascia overlying these muscles (eg, breast mass,
supraclavicular lymph nodes etc.).
a. Subjects with cutaneous/subcutaneous lesions must have lesions:
i. Non-visceral, measurable lesions by CT scan, MRI or calipers, and must have
a minimum of 1 lesion that is easily accessible for injection.
ii. Measure >= 1.5 cm in the smallest diameter.
iii. Be located in an anatomic location where MEDI1191 can be safely
administered, ie, not in close proximity to critical structures eg, carotid
artery, jugular vein, or other major blood vessels, nerve bundle, trachea or
other major airway tract.
10. For Part 1A and 1B, subjects must be willing to consent and undergo
pre-treatment biopsy of the lesion selected for MEDI1191 injection and if
clinically feasible, also, of a lesion not selected for injection. Subjects
enrolled in the pharmacodynamic expansion cohort for Parts 1A and 1B, must be
willing to consent and undergo pre-treatment tumor biopsy of an injected
(mandatory), and non-injected lesion (if clinically feasible).
11. Subjects in Parts 1A and 1B must be willing to undergo an on treatment
biopsy of previously injected and if clinically feasible un-injected lesions.

Part 1:
12. Histologic or cytologic confirmation of advanced solid tumor, including
NSCLC, squamous cell carcinoma of the head and neck, urothelial carcinoma, or
other tumors known to be responsive to checkpoint inhibitors, with the
exception of ocular melanoma and hepatocellular carcinoma.
13. Subjects must have received and have progressed on or be refractory to at
least 1 line of standard systemic therapy in the recurrent/metastatic setting.
Additionally, subjects must meet the following qualifications:
a. Parts 1A and 1B (IT injection of cutaneous or subcutaneous lesions): Must
have at least 1 site that is located in subcutaneous (eg, axillary) or
cutaneous or supraclavicular area and easily accessible for injection. At least
1 other lesion must meet definition of target lesion per RECIST v1.1.

All Parts (Reproductive Criteria):
14. Females of childbearing potential who are sexually active with a
nonsterilized male partner must use at least one highly effective method of
contraception (see Appendix A for definition of females of childbearing
potential and for a description of highly effective methods of contraception)
from screening, and must agree to continue using such precautions for 3 months
after the final dose of investigational product. It is strongly recommended for
the male partner of a female subject to also use male condom plus spermicide
throughout this period. Cessation of contraception after this point should be
discussed with a responsible physician. Periodic abstinence, the rhythm method,
and the withdrawal method are not acceptable methods of contraception.
a. Females of childbearing potential are defined as those who are not
surgically sterile (ie, surgical sterilization includes bilateral tubal
ligation, bilateral oophorectomy, or hysterectomy) or postmenopausal (defined
as 12 months with no menses without an alternative medical cause).
b. A highly effective method of contraception is defined as one that results in
a low failure rate (ie, less than 1% per year) when used consistently and
correctly.
c. Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she must inform her treating physician
immediately.
d. Female subjects must refrain from egg cell donation and breastfeeding while
on study and for 6 months after the final dose of investigational product.
15. Nonsterilized male subjects who are sexually active with a female partner
of childbearing potential must use a male condom with spermicide from Day 1
through 6 months after receipt of the final dose of investigational product. It
is strongly recommended for the female partner of a male subject to also use a
highly effective method of contraception throughout this period as described in
Appendix A. In addition, male subjects must refrain from sperm donation while
on treatment and for 6 months after the final dose of investigational product.
16. Subjects must have malignant melanoma or squamous cell histology tumors to
be eligible.

Please note that due to removing inclusion/ exclusion criteria not relevant for
the protocol conducted in The Netherlands, the numbers deviate from those in
the Main Protocol.

Any of the following would exclude the subject from participation in the study:
1. Prior IL-12 either alone or as part of a treatment regimen.
2. Concurrent enrollment in another clinical study within 30 days prior to
treatment administration, unless it is an observational (non interventional)
clinical study or the follow-up period of an interventional study.
3. Receipt of live attenuated vaccines within 30 days prior to the first dose
of study treatment. Subjects who receive study treatment should not receive
live or live attenuated vaccine during the study and 30 days after the last
dose of investigational products.
4. Known allergy or hypersensitivity to any component of MEDI1191 or durvalumab
formulations.
5. Active or prior documented autoimmune disorders within the past 5 years
prior to the first scheduled dose of study treatment. The following are
exceptions to this criterion:
a. Subjects with vitiligo or alopecia.
b. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement.
c. Any chronic skin condition that does not require systemic therapy.
d. Subjects with celiac disease controlled by diet alone.
6. History of primary immunodeficiency, other immune-deficiency states (eg,
myelodysplastic disorders, marrow failure states, human immunodeficiency virus
infection [even if viral load is undetectable], history of solid organ
transplant, bone marrow allograft), or active tuberculosis (in settings where
there is clinical or radiographic evidence of tuberculosis, active disease must
be excluded prior to enrollment in line with local practice).
7. History of coagulopathy resulting in uncontrolled bleeding, eg, hemophilia,
von Willebrand's disease. History of other bleeding disorders or a Grade >= 3
bleeding event within 3 months prior to first dose of investigational products.
8. Require continuous anticoagulation or antiplatelet therapy (except for <= 100
mg acetylsalicylic acid [ASA]) which cannot be interrupted for more than 7 days
for IT delivery of MEDI1191.
9. Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or
hormonal therapy for cancer. NOTE: Concurrent use of hormones for
noncancer-related conditions (eg, insulin for diabetes and hormone replacement
therapy for post-menopausal symptoms) or specific cancer-related conditions
(ie, LHRH-based hormonal therapy for prostate cancer with documented
progression) is acceptable. Local treatment of isolated lesions for palliative
intent is acceptable (eg, by local surgery or radiotherapy)
10. Receipt of any conventional or investigational anticancer therapy within 21
days or palliative radiotherapy within 7 days prior to the first dose of study
treatment. For subjects who have received prior immunotherapy, the following
additional exclusion criteria apply:
a. Received only one dose of prior immunotherapy agent alone or as part of a
combination regimen within 21 days.
b. Experienced a toxicity that led to permanent discontinuation of prior
immunotherapy
c. All AEs while receiving prior immunotherapy did not resolve to <= Grade 1 or
baseline prior to screening for this study.
d. Experienced a >= Grade 3 AE (including pneumonitis) or neurologic, ocular, or
cardiac AE of any grade while receiving prior immunotherapy (NOTE: Subjects
with an endocrine AE of any grade are permitted to enroll if they are stably
maintained on appropriate replacement therapy and are asymptomatic).
e. Required the use of additional immunosuppression other than corticosteroids
for the management of an AE, or experienced recurrence of an AE if re
challenged, or is currently requiring a maintenance dose of > 12 mg prednisone
or equivalent per day.
11. Any toxicity from prior therapy that has not completely resolved to <= Grade
1 or baseline at the time of consent. NOTE: Subjects with treatment-related
Grade 2 toxicities that are deemed stable or irreversible and not reasonably
expected to be exacerbated by any of the investigational products (eg, sensory
neuropathy, hearing loss) may be enrolled.
12. Current or prior use of immunosuppressive medication within 14 days prior
to the first dose of MEDI1191. The following are exceptions to this criterion:
a. Intranasal, topical, inhaled corticosteroids or local steroid injections
(eg, intraarticular injection).
b. Systemic corticosteroids at physiologic doses not to exceed 12 mg/day of
prednisone or equivalent.
c. Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication).
13. Have moderate or severe cardiovascular disease:
a. Presence of acute coronary syndrome including myocardial infarction or
unstable angina pectoris, other arterial thrombotic event including
cerebrovascular accident or transient ischemic attack within 6 months prior to
study entry.
b. New York Heart Association Class 3 or 4 congestive heart failure, or
uncontrolled hypertension (> 160 mmHg systolic and/or > 100 mmHg diastolic,
despite antihypertensive medication).
14. Any condition that, in the opinion of the investigator or sponsor, would
interfere with evaluation of the investigational product or interpretation of
subject safety or study results.
15. Uncontrolled intercurrent illness, including but not limited to, ongoing or
active bacterial, fungal or viral infections, interstitial lung disease,
serious gastrointestinal conditions associated with diarrhea, or psychiatric
illness/social situations that would limit compliance with study requirements,
substantially increase risk of incurring AEs or compromise the ability of
subject to give written informed consent.
16. Untreated, active hepatitis B or C as defined by seropositivity for
hepatitis B or C surface antigen (HBsAg, HCsAg) or positive hepatitis B core
(HBc) antibody.
a. Subjects with chronic hepatitis B, confirmed by the presence of anti-HBc, or
hepatitis C, confirmed by the presence of detectable hepatitis C virus (HCV)
RNA or anti-HCV antibody, receiving antiviral therapy are allowed to enroll if
disease has been controlled for at least 1 month prior to screening.
i. Controlled hepatitis B is defined as serum hepatitis B virus DNA < 2000
IU/mL by polymerase chain reaction (PCR).
ii. Controlled hepatitis C is defined as undetectable hepatitis C RNA by PCR
either spontaneously or in response to a successful prior course of
anti-hepatitis C therapy.
17. Major surgery (as defined by the investigator) within 4 weeks prior to
first dose of MEDI1191 or still recovering from prior surgery. NOTE: Minor
procedures (eg, placement of venous access devices, core needle biopsy) are
allowed if completed at least 24 hours prior to the first dose of MEDI1191.
18. Subjects with untreated active major depression with suicidal ideation
and/or plan.
19. Female subjects who are pregnant, lactating, or intend to become pregnant
during their participation in this study.