This is a Phase 1, open-label, multicenter study of continuous oral dosing of AZD4635
administered to patients with advanced solid malignancies. Dosing will be escalated until a
maximum-tolerated dose (MTD) is determined in patients. The MTD will be defined by
dose-limiting toxicity. The study design allows an escalation of dose with intensive safety
monitoring to ensure the safety of the patients. Expansion cohorts will further assess safety
and preliminary anti-tumor activity in a variety of advanced solid tumor malignancies. Other
dosing schedules and/or combinations may be evaluated based on the emerging PK and safety
The primary objectives of this study are to:
- Investigate the safety and tolerability of AZD4635 monotherapy when given orally (PO) to
patients with advanced solid malignancies.
- Investigate the safety, tolerability, and pharmacokinetics (PK) of AZD4635 monotherapy
capsule formulation when given to patients with advanced solid malignancies.
- Investigate the safety and tolerability of AZD4635 PO when given in combination with
durvalumab, durvalumab plus oleclumab, or docetaxel to patients with advanced solid
malignancies and to investigate the safety and tolerability of AZD4635 in combination
with abiraterone acetate or enzalutamide in patients with mCRPC.
- Define the maximum-tolerated dose (MTD) of AZD4635 in combination with durvalumab.
- Define the recommended Phase 2 dose (RP2D) of AZD4635 in combination with abiraterone
acetate or enzalutamide.
- Determine the safety, tolerability, and immune effects of AZD4635 when administered in
combination with durvalumab to patients with non-small cell lung cancer (NSCLC) who have
previously received immunotherapy (Phase 1b portion).
- Investigate the safety and tolerability of AZD4635 capsule formulation in combination
with durvalumab and oleclumab when given to patients with mCRPC or advanced solid tumor
- Define the RP2D of AZD4635 capsule formulation in combination with durvalumab and
oleclumab when given to patients with mCRPC or advanced solid tumor malignancy.
- Investigate the safety and tolerability of AZD4635 capsule formulation in combination
with docetaxel when given to patients with mCRPC or advanced solid tumor malignancy.
- Define the RP2D of AZD4635 capsule formulation in combination with docetaxel when given
to patients with mCRPC or advanced solid tumor malignancy.
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 or durvalumab plus oleclumab, in combination with
docetaxel, and in combination with either abiraterone acetate or with enzalutamide.
A capsule formulation of AZD4635 will be evaluated in 3 arms (arms CA, CB, and CC). An oral
nanoparticle suspension in water constituted extemporaneously by the patient will be
administered in all other treatment arms. Most patients who started therapy with the
nanoparticle suspension will transition to the capsule dosage form depending on the arm they
are assigned to and emerging data. Active patients in arms C, D, E, F, G, H, I, J, K, KD, and
L should be offered the option to transition to the capsule formulation at the discretion of
the Investigator in discussion with the Medical Monitor. Patients in study arms AA and AE
receiving AZD4635 as the nanoparticle suspension should change over to the capsule
formulation as soon as possible at the discretion of the Investigator.
The dose escalation arms are described as follows:
- Arms A, B, and C (dose escalation of AZD4635 monotherapy).
- Arms CA, CB, and CC. In arm CA, the safety, tolerability and PK of the capsule
formulation will be assessed in approximately 6 patients with advanced solid
malignancies to ensure at least 5 patients have evaluable pharmacokinetic sampling. An
additional 12 patients will be enrolled in this arm. Arm CB will assess the safety and
tolerability and determine the RP2D of the AZD4635 capsule plus durvalumab and oleclumab
in approximately 12 patients. Arm CC will assess the safety, tolerability and determine
the RP2D of AZD4635 capsule plus docetaxel in approximately 12 patients .
- 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 nanoparticle suspension formulation of AZD4635 as a single agent or in
combination with durvalumab.
● Arms EA and AA. Arms EA and AA [dose escalation of AZD4635 in combination with either
abiraterone acetate plus prednisone or enzalutamide in patients with metastatic
castrate-resistant prostate cancer (mRCPC)]. The AZD4635 plus hormonal therapy cohorts will
enroll concurrently. Patients who previously received abiraterone acetate, enzalutamide, or
apalutamide as part of their prior treatments for mCRPC may be enrolled to the enzalutamide
plus AZD4635 arm (Cohort EA) or the abiraterone acetate plus AZD4635 arm (Cohort AA) at the
discretion of the Investigator. Approximately 24 to 48 patients with mCRPC will be treated in
the AZD4635 plus hormonal therapy arms in order to establish the RP2D.
In Phase 1a approximately 90-132 patients will be treated with AZD4635 as a single agent or
in combination with durvalumab, durvalumab plus oleclumab, docetaxel, abiraterone acetate or
The second segment of the study, designated Phase 1b, will further assess the safety and
preliminary activity in the expansion arms described below.
- 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
- 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
- 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
- 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
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.
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 years
3. Weight ≥77 lbs (35 kg)
4. Availability of an archival tumor tissue sample. If archival tumor tissue is not
available, then tissue from a fresh biopsy can be used.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 w/ no clinical
deterioration over the prior 2 weeks (wks) and likely able to complete at least 9 wks
6. Normotensive or well controlled blood pressure (systolic <150 and diastolic <90) w/ or
without current anti-hypertensive treatment. If there is a diagnosis or history of
hypertension, patient must have adequately controlled BP on antihypertensive
medications as demonstrated by 2 BP measurements taken in the clinical setting by a
medical professional within 1 week (wk) prior to enrollment. Patients on
anti-hypertensive medication must be willing and able to check and record twice daily
BP readings for a minimum of 3 wks.
7. 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.
8. Male patients should be willing to use barrier contraception for the duration of the
study and for 3 months after treatment discontinuation.
9. Ability to swallow and retain oral medication.
Additional Inclusion Criteria for Phase 1a Arms AA and EA
1. Patients in Arms AA and EA must have metastatic prostate cancer w/ histological or
cytological confirmation. Note: Patient may have bone only metastatic 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 w/ gonadotropin-releasing hormone analogues
should continue this treatment during this study.)
- Patients must have received prior treatment w/ at least one of the hormonal agents
(abiraterone acetate, enzalutamide or apalutamide). Patients who received prior
apalutamide will be allocated to abiraterone acetate (Arm AA). Note: Prior
chemotherapy is allowed but not required.
- Patients must have evidence of disease progression.
Additional Inclusion Criteria for Phase 1a Arm CA
1. Patients in Arm CA must have a histologically/cytologically confirmed advanced solid
tumor malignancy that has received and progressed on standard-of-care therapy(ies).
Additional Inclusion Criteria for Phase 1a Arms CB and CC
1. Patients in Arms CB and CC may have metastatic prostate cancer w/ histological or
• Patient 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. Note: Patient with prostate cancer
may have bone-only metastatic disease.
• Patient must have-evidence of disease progression. Or
• Patients in Cohort CB must have a histologically/cytologically confirmed advanced
solid tumor malignancy that has received and progressed on standard-of-care
Or • Patients in Cohort CC should have a histologically/cytologically confirmed
advanced solid tumor malignancy suitable for treatment with docetaxel.
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 wks 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
- Patients must have advanced or metastatic NSCLC w/ histological or cytological
confirmation. Patients with known EGFR-activating mutations or ALK rearrangements
- Patient must have previously received one (but no more than one) line of previous
therapy w/ 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 w/ 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
• Patients must have metastatic prostate cancer w/ histological or cytological
- 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 w/ gonadotropin-releasing hormone
analog should continue this treatment during this study.
- Patients must have previously received and progressed on standard-of-care
- Approximately 60 out of 80 patients w/ mCRPC enrolled must have measurable
disease (approximately 30 out of 40 patients in each of the mCRPC arms 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
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
7. For other immune checkpoint naïve tumor patients (Arm L) all of the following must
- Patients w/ other immune checkpoint naïve histologically/ cytologically confirmed
advanced solid tumor type that has received and progressed on standard-of-care
1. Treatment with any of the following:
- Nitrosourea or mitomycin C within 6 wks 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 shorter). 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 recommended for patients w/ 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 wks prior to Day 1 of dosing and withheld throughout the study
until 2 wks 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 acetate arm (Arm AA) if
co-administration of a strong CYP3A4 or a CYP2D6 substrate with a narrow
therapeutic index is required during study treatment.
- Patient may not be assigned to an enzalutamide arm (Arm EA) if co-administration
of strong CYP2C8 inhibitor, strong or moderate CYP3A4 or CYP2C8 inducer, or
CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index is
required during study treatment.
- Ongoing treatment w/ Coumadin.
- Concomitant medications w/ another A1R antagonist that would increase risk of
seizure (e.g., theophylline or aminophylline).
- AZD4635 in the present study (i.e., dosing w/ AZD4635 previously initiated in a
different arm in this study), or prior therapy w/ AZD4635 or any other A2AR
- Ongoing corticosteroid use. NOTE: mCRPC patients assigned to an arm with
abiraterone acetate (Arm AA) should take prednisone as prescribed for
glucocorticoid replacement therapy and patients assigned to the docetaxel arm
(Arm CC) should take prophylactic dexamethasone (or equivalent) to prevent severe
- Major surgery (excluding placement of vascular access) within 4 wks of the first
dose of study treatment.
- Radiotherapy w/ a wide field of radiation within 4 wks or radiotherapy w/ a
limited field of radiation for palliation within 2 wks of the first dose of study
2. Patient w/ prior history of myocardial infarction, transient ischemic attack, or
stroke within 3 months prior to the scheduled first dose of oleclumab treatment (Arm
3. With the exception of alopecia, any unresolved toxicities from prior therapy greater
than CTCAE Grade 1 at the time of starting study treatment must be discussed with the
4. 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.
5. Significant mental illness in the 4-wk period preceding drug administration.
6. 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.
7. History or presence of another primary invasive malignancy except for:
• Malignancy treated w/ curative intent and w/ no known active disease ≥2 years before
the first dose of study drug and of low potential risk for recurrence.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
• Adequately treated carcinoma in situ without evidence of disease.
• Localized non-invasive primary under surveillance.
8. 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 arrhythmic
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. Patients receiving a
medication(s) known to prolong QT internval may be discussed w/ the Medical
Monitor or Sponsor for study approval.
- Ejection fraction <55% or less than the lower limit of normal of the
9. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:
• Absolute neutrophil count <1.5 x 10^9/L
- Platelet count <100 x 10^9/L
- Hemoglobin <90 g/L
- ALT and/or AST >2.5 x the upper limit of normal (ULN) if no demonstrable liver
metastases or >5 x ULN in the presence of liver metastases
- Total bilirubin >1.5 x ULN
- Creatinine >1.5 x ULN concurrent with creatinine clearance <50 mL/min
10. Refractory nausea and vomiting, chronic gastrointestinal diseases, or previous
significant bowel resection that would preclude adequate absorption of AZD4635.
11. Any patient w/ open oral ulceration(s) should avoid dosing with AZD4635 oral
12. Patients w/ severe hepatic impairment (Child-Pugh Class C) are not permitted to enroll
in the mCRPC plus hormone arms containing abiraterone acetate.
13. Organ transplant that requires the use of immunosuppressive treatment.
14. 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
- Psoriasis or eczema not requiring systemic treatment.
15. Patients w/ prior ≥Grade 3, serious, or life threatening immune-mediated reactions
following prior anti-PD-1 or other immune-oncology therapies.
16. History of hypersensitivity to AZD4635 or drugs w/ a similar chemical structure or
class to AZD4635.
17. Judgment by the Investigator or the Medical Monitor that the patient should not
participate in the study if the patient is unlikely to comply w/ study procedures,
restrictions, and/or requirements.