AZD9150 Plus Durvalumab Alone or in Combination With Chemotherapy in Patients With Advanced, Solid Tumours and in Patients With Non-Small-Cell Lung Cancer

This international, multicenter study was originally intended to be conducted in four parts,
designated as Parts A, B, C, and D. The protocol was amended in December 2018 to remove Parts
B and C. Parts B and C were intended to evaluate patients with locally advanced or metastatic
Stage IV NSCLC; however, these parts of the study will not be conducted.

Part A of this study will evaluate the safety and tolerability of durvalumab and AZD9150 with
and without selected chemotherapy regimens, and will include patients with advanced solid
malignancies that are refractory to standard therapy or for whom no standard of care (SOC)
regimen currently exists.

Part D will compare the relative bioavailability of the AZD9150 subcutaneous (SC) versus
intravenous (IV) formulations in patients with confirmed solid malignancies that are
refractory to standard therapy or for whom no SOC regimen currently exists. Approximately 50
to 62 PK-evaluable patients will be enrolled in Part D. Patients will be randomly assigned to
either SC or IV AZD9150. For Part D, the PK Analysis set will include all patients who
receive both study drugs (both AZD9150 and durvalumab) and have at least one PK sample
collection.

A complementary anti-tumour strategy will be used in this study with 2 immuno-therapeutics
applied to restore effective anti-tumour immunity at 2 distinct stages: promoting the
effector function of T-cell responses with an anti-PD-L1 mAb, durvalumab, while hindering
immune escape in the tumour bed with AZD9150. In addition, chemotherapy will be added to this
combination to investigate possible future enhancement of response. In preclinical models,
conventional platinum-based chemotherapy has been shown to induce T-cell activation through
the release of tumour-specific antigens during cancer cell death. The elimination of
persistent tolerogenic tumour antigen environment via chemotherapy-induced debulking may also
play a role in generating an effective immune response. In this setting, immunotherapy has
the potential to mount an ongoing and dynamic immune response that can kill tumour cells for
an extended time.

Part A of the study will be conducted in five arms, designated Arms A1, A2, A3, A4, and A5.
The primary objective of Part A is to assess the safety and tolerability, and determining the
maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of AZD9150 plus durvalumab in
patients with advanced solid malignancies. In addition, another primary objective is to
assess the safety and tolerability, and determine the maximum tolerated dose/recommended
phase 2 dose (MTD/RP2D) of AZD9150 plus durvalumab in combination with standard chemotherapy
regimens in patients with advanced solid malignancies. Approximately 30 to 78 DLT-evaluable
patients will be enrolled in Part A.

In Arm A1, patients will receive AZD9150 by (IV) infusion Q2W + durvalumab by IV infusion
Q4W. Chemotherapy will not be given in Arm A1.

Arm A2 patients will receive AZD9150 IV QW + durvalumab IV Q3W, cisplatin by slow IV infusion
over 1-4 hours on Day 1 + 5-fluorouracil (5FU) by continuous IV infusion over 96 hours (Days
1 through 4, repeated every 3 weeks for up to 18 weeks). In Arm A2 there will be a AZD9150 +
chemotherapy lead-in period prior to durvalumab dosing. The last chemotherapy dose will be
given in Week 15. After discontinuation of chemotherapy the regimen will include AZD9150 IV
QW + durvalumab IV Q4W. Administration of durvalumab will continue Q3W through Week 19, at
which time the schedule will switch to Q4W (e.g., Week 23, 27, 31, etc.).

Depending on the results from Arm A2, Arm A3 may not be conducted. If the Safety Review
Committee (SRC) decides to open Arm A3, the SRC will determine the starting dose. Patients
will be administered one of the following 4 chemotherapy regimens in combination with AZD9150
and durvalumab appropriate for their tumour type:

- In Arm A3, patients will receive cisplatin by slow IV infusion over 1-4 hours on Day 1 +
5FU by continuous IV infusion over 96 hours (Days 1 through 4, repeated every 3 weeks
for up to 18 weeks).

- In Arm A4, patients will receive gemcitabine by IV infusion over 30 minutes on Days 1
and 8 every 3 weeks for 12 to 18 weeks, plus either:

- for cisplatin-eligible patients: cisplatin IV over 30 minutes on Day 1 (every 3
weeks for up to 12 to 18 weeks); or

- for cisplatin-ineligible patients: carboplatin IV over 30 to 60 minutes on Day 1
(every 3 weeks for up to 12 to 18 weeks).

- In Arm A5, patients will receive carboplatin at AUC 5 IV over 30 to 60 minutes on Day 1
+ nab-paclitaxel IV over 30 to 40 minutes on Days 1, 8, and 15 (every 3 weeks for up to
12 to 18 weeks).

There will be an AZD9150 7-day lead-in period (termed Week 0) in all arms in all parts of the
study. AZD9150 will be given IV on Days 1,3, and 5 of the lead-in week. When chemotherapy is
administered, the dosing of chemotherapy will also commence during the lead-in period with
AZD9150. In Arm A2 of Part A, dosing with AZD9150 IV, durvalumab, and chemotherapy will
commence on Day 1 of Week 0. In Part D, dosing with AZD9150 IV or SC will commence on Day 1
of Week 0.

Inclusion Criteria

Subjects are eligible to be included in the study only if all of the following inclusion
criteria and none of the exclusion criteria apply.

1. Signed and dated informed consent. For inclusion in the optional pharmacogenetic
research, patients must provide informed consent for the genetic sampling and
analyses.

2. ≥ 18 years of age.

3. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

4. Minimum life expectancy of 12 weeks

5. Part A of the study will include patients that have histological confirmation of a
solid malignancy [other than Hepatocellular Carcinoma (HCC)] that is refractory to
standard therapy or for which no standard of care regimen currently exists.

6. Part D of the study will include patients with histological confirmation of a solid
malignancy (other than HCC) that are refractory to standard therapy of for which no
standard of care regimen currently exists.

7. Willing to undergo mandatory biopsy at screening and on treatment. Part A only: the
first 3 subjects in each arm are exempt from this requirement. Patients in Part D are
exempt from this biopsy requirement.

8. At least one lesion, not previously irradiated, that can be accurately measured at
baseline as ≥10 mm in the longest diameter (except lymph nodes that must have short
axis ≥15 mm) with computerised tomography (CT) or magnetic resonance imaging (MRI)
that is suitable for accurate repeated measurements.

9. Females should be using adequate contraceptive measures, should not be breast feeding,
and must have a negative pregnancy test prior to start of dosing if of child-bearing
potential or must have evidence of non-child-bearing potential by fulfilling one of
the following criteria at screening:

- Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least
12 months following cessation of all exogenous hormonal treatments

- Women under 50 years old would be considered postmenopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and with luteinising hormone and follicle-stimulating hormone levels
in the post-menopausal range for the institution

- Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
oophorectomy, or bilateral salpingectomy, but not tubal ligation.

10. Male patients must be surgically sterile or using an acceptable method of
contraception (defined as barrier methods in conjunction with spermicides) for the
duration of the study (from the time they sign consent) and for 20 weeks after the
last dose of study treatments.

Exclusion Criteria

Patients should not enter the study if any of the following exclusion criteria are
fulfilled.

1. Involvement in the planning and/or conduct of the study (applies to AstraZeneca and/or
Sarah Cannon Development Innovations staff and/or staff at the study site).

2. Previous enrolment in the present study.

3. Herbal preparations are not allowed throughout the study. These herbal medications
include but are not limited to St. John's wort, kava, ephedra (mahung), gingko biloba,
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng. Patients should stop
using herbal medications 7 days prior to the first dose of study treatment.

4. Brain metastases or spinal cord compression unless asymptomatic and not requiring
steroids for at least 14 days prior to start of study treatment.

5. With the exception of alopecia and haemoglobin (Hb) ≥ 9 mg/dL and < 10 mg/dL, any
unresolved toxicities from prior therapy CTCAE Grade > 1 at the time of starting study
treatment.

6. Active interstitial lung disease (ILD)/pneumonitis or a prior history of
ILD/pneumonitis requiring treatment with steroids.

7. Patients receiving any concurrent chemotherapy, radiotherapy, immunotherapy, or
biologic, or hormonal therapy for cancer.

- Concurrent use of hormones for noncancer-related conditions (e.g., insulin for
diabetes and hormone replacement therapy) is acceptable. The dose of systemic
corticosteroids must not exceed 10 mg of prednisone equivalent.

- Patients in Part A and Part D with radically-treated prostate cancer may continue
androgen deprivation therapy (ADT).

8. Patients must have completed any previous cancer-related treatments before enrolment.
The following intervals between the end of the prior treatment and first dose of study
drug must be observed:

- Port-a-cath placement: no waiting is required

- Minor surgical procedures (as defined by the Medical Monitor): 7 postoperative
days

- Major surgery (as defined by the Medical Monitor): ≥4 weeks

- Radiotherapy: ≥4 weeks (patients who receive palliative radiation for nontarget
tumour lesions need not be subjected to this washout period and can be enrolled
immediately)

- Chemotherapy: ≥ 21 days or 5 half-lives (whichever is longer) from the first dose
of study drug

- Immunotherapy and/or anticancer therapy with agents including mAbs ≥4 weeks

- Current or prior use of immunosuppressive medication within 14 days before first
dose of durvalumab The following are exceptions to this criterion:

- Use of intranasal, inhaled, topical corticosteroids, local steroid
injections (e.g., intra articular injections)

- Systemic corticosteroids at physiologic doses below 10 mg/day of prednisone
or equivalent is permitted

- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication) are permitted

9. For Part A and Part D patients who have received more than 3 prior cytoreductive
chemotherapy regimens.

10. Has active or prior documented autoimmune disease within the past 2 years with the
exceptions of vitiligo, Graves' Disease, and/or psoriasis not requiring systemic
treatment

11. Has active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis)

12. Has a history of primary immunodeficiency

13. Has undergone an organ transplant that requires use of immunosuppressive treatment

14. Any of the following cardiac criteria:

- Mean resting corrected QT interval (QTc) calculated using Fridericia's formula
(QTcF) of >450 msec for males and >470 msec for females obtained from 3
electrocardiograms (ECGs) taken over 5 minutes

- Any clinically important abnormalities in rhythm, conduction or morphology of a
resting ECG, e.g., complete left bundle branch block, third degree heart block,
that in the opinion of the Investigator renders the patient unsuitable for
participation in the study

- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalaemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years-of-age

- Any concomitant medication with known or possible risk of prolonging the QT
interval.

15. Inadequate organ and marrow function as demonstrated by any of the following
laboratory values. Transfusions intended to elevate any parameters below solely for
the intent of meeting study eligibility are not permitted.

- Leukocytes <3.0 x 10(exp 9)/L

- Absolute neutrophil count <1.5 x 10(exp 9)/L

- Platelet count <100 x 10(exp 9)/L

- Haemoglobin <90 g/L

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 times the
upper limit of normal (ULN) if no demonstrable liver metastases or >5 times ULN
in the presence of liver metastases

- Total bilirubin >1.5 times ULN if no liver metastases or 3 times ULN in the
presence of liver metastases or documented Gilbert's Syndrome (unconjugated
hyperbilirubinaemia)

- Creatinine outside normal limits OR, if creatinine outside normal limits, a
creatinine clearance <60 mL/min (measured by 24-hour urine collection or
calculated by Cockcroft and Gault equation (Cockcroft and Gault 1976).

16. Has a history of allergic reactions attributed to the study treatments (AZD9150 or
durvalumab), assigned chemotherapy agents, their compounds, or agents of similar
chemical or biologic composition (e.g., antibody therapeutics)

17. Suffers from a comorbidity that in the opinion of the Investigator or Medical Monitor
renders the patient unsuitable for participation in the study. Such comorbidity may
include, but is not limited to, uncontrolled intercurrent illness such as active
infection, severe active peptic ulcer disease or gastritis, myocardial infarction
within 6 months before entry, congestive heart failure, symptomatic congestive heart
failure, active cardiomyopathy, unstable angina pectoris, cardiac arrhythmia,
uncontrolled hypertension, or psychiatric illness/social situations that would limit
compliance with study requirements.

18. As judged by the Investigator, has any evidence of severe or uncontrolled diseases, or
has an active viral infection of human immunodeficiency virus (HIV), human papilloma
virus (HPV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV)].

19. Active infection including tuberculosis (clinical evaluation that included clinical
history, physical examination and radiographic findings, and tuberculosis testing in
line with local practice).

20. Has received a live attenuated vaccine within 28 days before the first dose of study
drug

21. Judgment by the Investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions, and
requirements.