A Phase 1, Open-Label, Multicenter Study to Assess Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-Tumor Activity of Ascending Doses of AZD4635 Both as Monotherapy and in Combination in Patients With Advanced Solid Malignancies
A Phase 1, Open-Label, Multicenter Study to Assess Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-Tumor Activity of Ascending Doses of AZD4635 Both as Monotherapy and in Combination 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:
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 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.
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.
Inclusion Criteria
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.
Age ≥18 years
Weight ≥77 lbs (35 kg)
Availability of an archival tumor tissue sample. If archival tumor tissue is not available, then tissue from a fresh biopsy can be used.
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.
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.
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:
Male patients should be willing to use barrier contraception for the duration of the study and for 3 months after treatment discontinuation.
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.
Additional Inclusion Criteria for Phase 1a Arm CA
Additional Inclusion Criteria for Phase 1a Arms CB and CC
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
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).
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.
For post immunotherapy patients with NSCLC (Arms F and G) all of the following must apply:
For other post-immunotherapy patients (Arm H) all of the following must apply:
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.
For immune checkpoint naïve patients (Arms K and KD) all of the following must apply:
For other immune checkpoint naïve tumor patients (Arm L) all of the following must apply:
Exclusion Criteria
Treatment with any of the following:
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).
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.
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.
Significant mental illness in the 4-wk period preceding drug administration.
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.
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.
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.
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
Refractory nausea and vomiting, chronic gastrointestinal diseases, or previous significant bowel resection that would preclude adequate absorption of AZD4635.
Any patient w/ open oral ulceration(s) should avoid dosing with AZD4635 oral suspension.
Patients w/ severe hepatic impairment (Child-Pugh Class C) are not permitted to enroll in the mCRPC plus hormone arms containing abiraterone acetate.
Organ transplant that requires the use of immunosuppressive treatment.
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:
Patients w/ prior ≥Grade 3, serious, or life threatening immune-mediated reactions following prior anti-PD-1 or other immune-oncology therapies.
History of hypersensitivity to AZD4635 or drugs w/ a similar chemical structure or class to AZD4635.
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.