This is a phase Ib/II, open-label multicentre study to assess the safety, tolerability,
pharmacokinetics and preliminary anti-tumour activity of AZD9150 plus durvalumab alone or in
combination with chemotherapy in patients with advanced, solid tumours and subsequently in
patients with non-small-cell lung cancer (NSCLC).
This international, multicenter study will be conducted in three parts, designated A, B, and
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 5 arms. The primary objective of Part A is to assess
the safety, tolerability, and finding the maximum tolerated dose/recommended phase 2 dose
(MTD/RP2D) of AZD9150 given every two weeks (Q2W) plus durvalumab given every four weeks
(Q4W) in patients with advanced solid malignancies. In addition, the primary objective is to
assess the safety, tolerability, and finding 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 dose-limiting toxicity
(DLT)-evaluable patients will be enrolled in this arm.
Part B will be conducted in 2 arms and randomised 1:1. The primary objective of Part B is to
evaluate the objective response rate (ORR) of durvalumab in combination with AZD9150 at
different dosing schedules in patients with non-small-cell lung cancer (NSCLC). Approximately
90 efficacy-evaluable patients will be enrolled in this arm.
Part C will be one single arm. The primary objective of Part C is to evaluate the objective
response rate (ORR) of durvalumab and AZD9150 with chemotherapy in 1st-line non-small-cell
lung cancer (NSCLC) patients. Approximately 45 efficacy-evaluable patients will be enrolled
in this arm.
- An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and a
minimum life expectancy of 12 weeks
- Part A of the study will include patients that have histological confirmation of a
solid malignancy (other than HCC) that is refractory to standard therapy or for which
no standard of care regimen currently exists.
- Parts B of the study will include patients with histological or cytological
confirmation diagnosis of locally advanced or metastatic Stage IV NSCLC.
- Part C of the study will include patients with histological or cytological
confirmation diagnosis of locally advanced or metastatic Stage IV 1st-line NSCLC (for
which the patient has not received therapy).
- Willing to undergo mandatory biopsy at screening and on treatment. Part A only: the
first 3 subjects in each cohort are exempt from this requirement.
- 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.
- 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 childbearing
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 luteinizing 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.
- 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
- For inclusion in the optional PGx research, patients must provide informed consent for
the genetic sampling and analyses.
- 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).
- Previous enrolment in the present study.
- For Parts B and C, patients who received previous anti- PD-1, anti-PD-(L)1 treatment
- Brain metastases or spinal cord compression unless asymptomatic and not requiring
steroids for at least 14 days prior to start of study treatment
- Active interstitial lung disease (ILD)/pneumonitis or a prior history of
ILD/pneumonitis requiring treatment with steroids.
- For Part B and Part C, patients with tumors bearing genetic abnormalities for which
health authority-approved targeted therapies exist will not be enrolled; e.g, patients
with mutations including but not limited to ROS rearrangements, BRAF V600E, EGFR
mutations or ALK translocation patients will not be considered eligible
- For part B and part C, Presence of other active invasive cancers other than NSCLC or
history of treatment for invasive cancer other than NSCLC in the past 3 years.
- Previously treated in situ carcinoma (i.e., noninvasive)
- Cervical carcinoma Stage 1B or less
- Noninvasive basal cell and squamous cell skin carcinoma
- Radically treated prostate cancer (prostatectomy or radiotherapy) with normal
prostate-specific antigen, and not requiring ongoing antiandrogen hormonal therapy.
- 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)
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 Investigator): 7 postoperative days
- Major surgery (as defined by the Investigator): ≥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: within 21 days or 5 half-lives (whichever is longer) from enrolment
- Immunotherapy and/or investigational anticancer therapy with agents including mAbs :
- Use of intranasal and inhaled corticosteroids or systemic corticosteroids at
physiologic doses not to exceed 10 mg/day of prednisone or equivalent is permitted.
- Part A patients who have received more than 3 prior cytoreductive chemotherapy
- Has active or prior documented autoimmune disease within the past 2 years with the
exceptions of vitiligo, Grave's disease, and/or psoriasis not requiring systemic
- Has active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
- Has a history of primary immunodeficiency
- Has undergone an organ transplant that requires use of immunosuppressive treatment
- 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 render the patient unsuitable for participation in
- 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, or any concomitant
medication known to prolong the QT interval
- 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 109/L
- Absolute neutrophil count <1.5 x 109/L
- Platelet count <100 x 109/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
- 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).
- 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)
- Suffers from a comorbidity that in the opinion of the Investigator 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
- As judged by the Investigator, has any evidence of severe or uncontrolled diseases
such as active bleeding diatheses, 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)
- Has a known history of tuberculosis
- Has received a live attenuated vaccine within 28 days before the first dose of study
- 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