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

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 data.

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 malignancy.
* 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 enzalutamide.

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.\[40 patients\]
* 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 minimize 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.

Eligibility Criteria:
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 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 of treatment.
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 cytological confirmation:

   • 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 therapy(ies).

   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

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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 apply:

   * Patients must have advanced or metastatic NSCLC w/ 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 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 apply:

   • Patients must have metastatic prostate cancer w/ 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 w/ 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 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 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 w/ 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 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 antagonist.
   * 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 hypersensitivity reactions.
   * 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 treatment.
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 CB).
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 Medical Monitor.
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 disease.

   • 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 institutional standard.
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 suspension.
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 replacement.
    * 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.