A Phase 1 Clinical Study of AZD4635 in Patients With Advanced Solid Malignancies

The study will be conducted in two segments. The first segment of the study, designated Phase
1a, will be a dose escalation design in order to assess the safety, tolerability,
pharmacokinetics (PK), and preliminary anti-tumor activity of ascending doses of AZD4635 as
monotherapy, in combination with durvalumab, and in combination with either abiraterone or
with enzalutamide. The dose escalation arms are described as follows:

- Arms A, B, and C (dose escalation of AZD4635 monotherapy).

- Arms D and E [dose escalation of AZD4635 in combination with durvalumab anti-programmed
death-ligand 1 (PD-L1)].

Arms A through E enrolled 38 patients in Phase 1a in order to establish the Recommended Phase
2 Dose (RP2D) of the mix and drink formulation of AZD4635 as a single agent or in combination
with durvalumab.

● Arms EA and AA. The safety, tolerability and PK of AZD4635 will be tested in combination
with either abiraterone or enzalutamide in patients with metastatic castrate-resistant
prostate carcinoma (mCRPC). The AZD4635 plus hormonal therapy cohorts will enroll
concurrently. Patients who previously received abiraterone as part of their first-line
treatment for mCRPC will be enrolled to the enzalutamide plus AZD4635 cohort (Arm EA).
Patients who previously received enzalutamide or apalutamide as part of their first-line
treatment for mCRPC will be enrolled to an abiraterone plus AZD4635 cohort (Arm AA). The
pharmacokinetic parameters of single-dose AZD4635 monotherapy will be characterized at least
24 hours prior to Cycle 1 Day 1 administration of the combined treament (AZD4635 plus
hormonal therapy). The PK parameters of AZD4635 plus hormonal therapy will also be
characterized on Day 15 of Cycle 1. Cycle 1 and Cycle 2 will be 3 weeks in duration to assess
dose-limiting toxicity (DLT) and safety. Beyond Cycle 2, cycles will be 4 weeks long in order
to align with assessments for all other cohorts. Once a preferred doses(s) in the combination
setting is determined, up to 6 additional patients with metastatic castration-resistant
prostate cancer (mCRPC) may be enrolled per combination to explore further the safety,
tolerability, PK, and biological activity at the selected doses. Approximately 24 to 48
patients with mCRPC will be treated in the AZD4635 plus hormonal therapy cohorts yielding a
total of approximately 48-86 patients to be treated in Phase 1a.

The Phase 1b portion of the study consists of expansion arms in tumour types where there is a
rationale for potential efficacy of the study treatment(s) (e.g., high expression of cluster
differentiation 73 [CD73]). The arms to be explored are:

- Arm F - AZD4635 in combination with durvalumab. Post-immunotherapy non-small cell lung
cancer (NSCLC). [15 patients]

- Arm G - AZD4635 monotherapy. Post-immunotherapy NSCLC. [15 patients]

- Arm H - AZD4635 monotherapy. Immune checkpoint resistant malignancies, previously
treated with approved immunotherapy and progressed or responded and then stopped
responding (e.g. renal cell carcinoma, head and neck carcinoma, or MSI high cancers
which have approved settings for anti-PD-1 treatment).[20 patients]

- Arm I - AZD4635 in combination with durvalumab. Immune checkpoint naïve mCRPC.[40
patients]

- Arm J - AZD4635 monotherapy. Immune checkpoint naïve CRPC. [40 patients]

- Arm K - AZD4635 monotherapy. Immune checkpoint naïve colorectal carcinoma (CRC). CRC,
excluding MSI high, which has not been treated with immune checkpoint inhibitors.[20
patients]

- Arm KD - AZD4635 in combination with durvalumab. Immune checkpoint naïve CRC. CRC,
excluding MSI high, which has not been treated with immune checkpoint inhibitors.[20
patients]

- Arm L - AZD4635 monotherapy. Other solid tumours immune checkpoint naïve.
Relapsed/refractory tumors which have not been treated with immune checkpoint
inhibitors.[20 patients]

Patients will be randomly assigned between open-label arms with AZD4635 monotherapy and
AZD4635 combined with durvalumab in NSCLC (Arms F/G) and mCRPC (Arms I/J) in order to avoid
bias.

Patients with CRC, excluding MSI high, will be enrolled to AZD4635 monotherapy (Arm K) and
AZD4635 combined with durvalumab (Arm KD) in patients with CRC.

Some arms will have a mandatory biopsy subgroup to ensure sufficient tissue is collected to
assess the mechanism of action in tissue without excluding patients with nonbiopsiable
disease. Biopsies are optional in all other arms.

Inclusion Criteria

1. Patient must consent to the study and provide a signed and dated, written informed
consent document prior to any study-specific procedures, sampling, or analyses.

2. Age ≥ 18.

3. Availability of an archival tumor tissue sample. If archival tumour tissue is not
available, then tissue from a fresh biopsy can be used.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 with no clinical
deterioration over the previous 2 weeks and likely able to complete at least 9 weeks
of treatment.

5. Normotensive or well controlled blood pressure (<140/90) with or without current
antihypertensive treatment. If there is a diagnosis or history of hypertension,
patient must have adequately controlled BP on a maximum of 2 antihypertensive
medications, as demonstrated by 2 BP measurements taken in the clinical setting by a
medical professional within 1 week prior to enrollment. It is strongly recommended
that patients who are on antihypertensive medications be followed by a cardiologist or
a primary care physician for management of BP while on the study. Patients on a
hypertensive medication must be willing and able to check and record twice daily BP
readings for a minimum of 3 weeks.

6. Females should be using adequate contraceptive measures from the time of screening
until 3 months after study discontinuation, should not be breast feeding and must have
negative pregnancy test prior to the start of dosing, 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 amenorrheic for at least
12 months following cessation of all exogenous hormonal treatments.

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

- Women under 50 years-of-age will be considered postmenopausal if they have been
amenorrheic for at least 12 months following the cessation of exogenous hormonal
treatments, and have serum follicle-stimulating hormone and luteinizing hormone
levels in the postmenopausal range for the institution.

7. Male patients should be willing to use barrier contraception for the duration of the
study and for 3 months after treatment discontinuation.

8. Ability to swallow and retain oral medication.

Additional Inclusion Criteria for Phase 1a Combination Arms AA and EA.

1. Patients in Arms AA and EA must have metastatic prostate cancer with histological or
cytological confirmation. N.B. Patient may have bone only metatastic disease.

- Patients must be castrate-resistant (i.e., developed progression of metastases
following surgical castration or during medical androgen ablation therapy). (Patients
receiving medical castration therapy with gonadotropin-releasing hormone analogues
should continue this treatment during this study.)

- Patients must have received prior treatment with one of the hormonal agents
abiraterone, enzalutamide or apalutamide. Patients who received prior apalutamide will
be allocated to abiraterone. Only patients with one prior hormonal agent will be
permitted. N.B. Prior chemotherapy is allowed but not required.

- Patients must have evidence of disease progression.

Additional Inclusion Criteria for Phase 1b

1. Patients must have disease that is suitable for repeated measurement, either: a) at
least one lesion that can be accurately assessed at baseline by computed tomography
(CT), magnetic resonance imaging (MRI) or X-ray, that is suitable for repeated
measurement (RECIST v1.1), or b) for patients with mCRPC (Arms I and J), patients must
have measurable PSA above normal limits (per local ranges).

2. A minimum of 10 patients with mCRPC, CRC and 'Other' tumors will be required to have a
site of disease that is safely accessible for biopsy (paired) upon enrollment.
Accessible lesions are defined as those which are biopsiable (at screening) and
amenable to repeat biopsy (after 2 weeks of monotherapy), unless clinically
contraindicated. In the case that the second sample is not taken, the patient will
remain in the study and there will be no penalty or loss of benefit to the patient and
they will not be excluded from other aspects of the study. The tumor-specific cohorts
will be closely monitored to ensure the desired number of biopsiable patients are
enrolled. The requirement for biopsies must be made clear to each patient at the time
of initial approach by the Investigator.

3. For post immunotherapy patients with NSCLC (Arms F and G) all of the following must
apply:

- Patients must have advanced or metastatic NSCLC with histological or cytological
confirmation. Patients with known EGFR-activating mutations or ALK rearrangements
are excluded.

- Patient must have previously received one (but no more than one) line of previous
therapy with an anti-PD-1/PD-L1 mAb therapy either alone or in combination and
have either progressed or responded and then stopped responding.

4. For other post-immunotherapy patients (Arm H) all of the following must apply:

- Patients must have an immune checkpoint resistant malignancy (for example, RCC,
head and neck carcinoma, or MSI high cancers which have approved settings for
anti-PD1 treatment), confirmed histologically or cytologically.

- Patients must have previously received at least one line (and not more than 2
lines) of previous therapy with an anti-PD-1/PD-L1 mAb therapy, either alone or
in combination and have either progressed or responded and then stopped
responding.

5. For immune checkpoint naïve CRPC patients (Arms I and J) all of the following must
apply:

- Patients must have metastatic prostate cancer with histological or cytological
confirmation.

- Patients must be castrate-resistant (i.e., developed progression of metastases
following surgical castration or during medical androgen ablation therapy).
Patients receiving medical castration therapy with gonadotropin-releasing hormone
analog should continue this treatment during this study.

- Patients must have previously received and progressed on standard-of-care
therapy(ies).

- Approximately 60 out of 80 patients with mCRPC enrolled must have measurable
disease (approximately 30 out of 40 patients in each of the mCRPC I and J) that
is suitable for repeated measurement (RECIST v1.1). Enrollment will be monitored
to ensure the required number of patients with measurable disease enter the
study.

6. For immune checkpoint naïve patients (Arms K and KD) all of the following must apply:

- Patients must have immune checkpoint naïve histologically/cytologically confirmed
advanced or metastatic colorectal carcinoma (CRC).

- Patients must have previously received and progressed on at least 1 prior
chemotherapy regimen.

7. For other immune checkpoint naïve tumor patients (Arm L) all of the following must
apply:

- Patients with other immune checkpoint naïve histologically/ cytologically
confirmed advanced solid tumor type that has received and progressed on
standard-of-care therapy(ies).

Exclusion Criteria

1. Treatment with any of the following:

- Nitrosourea or mitomycin C within 6 weeks of the first dose

- Any systemic anti-cancer chemotherapy, small molecule, biologic, or hormonal
agent from a previous treatment regimen or clinical study within 21 days or 5
half-lives (whichever is longer). At least 7 days must have elapsed between the
last dose of such agent and the first dose of study drug. EXCEPTION:
Androgen-deprivation therapy is permitted for patients with prostate cancer.

- Enrollment into another therapeutic clinical trial. EXCEPTION: Patients are
allowed to participate in investigational imaging or non-therapeutic studies.

- Patient has had Rx or non-Rx drugs or other products known to be sensitive BCRP
or OAT1 substrates or to be potent inhibitors/inducers of CYP1A2, which cannot be
discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the study
until 2 weeks after the last dose of AZD4635.

- Herbal preparations/medications are not allowed throughout the study, including
but not limited to St. John's Wort, kava, ephedra (ma huang), gingko biloba,
dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Patients should stop
using these herbal medications 7 days prior to the first dose of AZD4635.

- Patient may not be assigned to abiraterone arms if co-administration of a strong
CYP3A4 or a CYP2D6 substrate is required during study treatment.

- Patient may not be assigned to enzalutamide arms if requires co-administration of
strong CYP2C8, strong or moderate CYP3A4 or CYP2C8 inducers, CYP3A4, CYP2C9, and
CYP2C19 substrates during study treatment.

- Ongoing treatment with Coumadin.

- Concomitant medications with another A1R antagonist that would increase risk of
seizure (e.g., theophylline or aminophylline).

- AZD4635 in the present study (i.e., dosing with AZD4635 previously initiated in a
different arm in this study), or prior therapy with AZD4635 or any other A2AR
antagonist.

- Ongoing corticosteroid use. NOTE: mCRPC patients assigned to an arm with
abiraterone treatment should take prednisone as prescribed for glucocorticoid
replacement therapy.

- Major surgery (excluding placement of vascular access) within 4 weeks of the
first dose of study treatment.

- Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a
limited field of radiation for palliation within 2 weeks of the first dose of
study treatment.

2. With the exception of alopecia, any unresolved toxicities from prior therapy greater
than CTCAE Grade 1 at the time of starting study treatment.

3. History of seizures, central nervous system tumors or CNS metastasis. Due to the
incidence of silent CNS metastases in patients with advanced NSCLC, such patients must
undergo mandatory screening with brain MRI or CT scan to determine eligibility.

4. Significant mental illness in the 4-week period preceding drug administration.

5. As judged by the investigator, any evidence of severe or uncontrolled systemic
disease, including uncontrolled hypertension, active bleeding diatheses, or active
infection, including hepatitis B, hepatitis C, and human immunodeficiency virus.
Screening for chronic conditions is not required.

6. Any of the following cardiac criteria:

- Mean resting corrected QT interval (QTcF) >470 msec obtained from 3 ECGs.

- Any clinically important abnormalities in rhythm, conduction, or morphology of
resting ECGs, e.g., complete left bundle branch block, third degree heart block.

- Any factors that increase the risk of QTc prolongation or risk of rrhythmic
events such as heart failure, hypokalemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years-of-age, or
any concomitant medication known to prolong the QT interval

- Ejection fraction < 55% or less than the lower limit of normal of the
institutional standard.

7. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:

- Absolute neutrophil count < 1.5 x 10 (exp9)/L

- Platelet count < 100 x 10 (exp9)/L

- Hemoglobin <90 g/L

- ALT and/or 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

- Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min

8. Refractory nausea and vomiting, chronic gastrointestinal diseases, or previous
significant bowel resection that would preclude adequate absorption of AZD4635.

9. Any patient with open oral ulceration(s) should avoid dosing with AZD4635 oral
suspension.

10. Patients with severe hepatic impairment (Child-Pugh Class C) are not permitted to
enroll in the mCRPC plus hormone arms containing abiraterone.

11. Organ transplant that requires the use of immunosuppressive treatment.

12. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis, Crohn's disease], diverticulitis, celiac
disease, systemic lupus erythematous, Wegner's syndrome, myasthenia gravis, Grave's
disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis,
autoimmune nephritis or nephropathy, etc.) within the past 3 years prior to the start
of treatment. The following are exceptions to this criterion:

- Vitiligo or alopecia.

- Hypothyroidism (e.g., following Hashimoto's disease) stable on hormone
replacement

- Psoriasis or eczema not requiring systemic treatment.

13. Patients with prior ≥ Grade 3, serious, or life threatening immune-mediated reactions
following prior anti-PD-1 or other immune-oncology therapies.

14. History of hypersensitivity to AZD4635 or drugs with a similar chemical structure or
class to AZD4635.

15. Judgment by the Investigator or the Medical Monitor that the patient should not
participate in the study if the patient is unlikely to comply with study procedures,
restrictions, and/or requirements.