This is an open-label, multicentre, multi-drug, biomarker-directed Phase 2 platform study in
patients with advanced non-small cell lung cancer (NSCLC) harbouring an epidermal growth
factor receptor (EGFR)-sensitizing mutation whose disease has progressed on first-line
monotherapy with osimertinib.Treatment options for these patients are limited. Novel
treatments for these patients are urgently required.
This study is modular in design, allowing evaluation of the efficacy, safety and tolerability
of multiple study treatments.
Inclusion criteria applicable to all study treatment modules (Groups A/B):
- Non-Small Cell Lung Cancer (NSCLC) with the following features:
- Locally advanced or metastatic disease (i.e. advanced NSCLC) not amenable to
curative surgery or radiotherapy at study entry.
- Histologically or cytologically confirmed adenocarcinoma of the lung harbouring
epidermal growth factor receptor (EGFR) mutation(s) known to be associated with
tyrosine kinase inhibitors (TKI) sensitivity at diagnosis.
- Received only 1 line of therapy, with single-agent osimertinib, for advanced
NSCLC, with clinical benefit as judged by investigator discretion.
- Evidence of radiological disease progression on first-line monotherapy with
osimertinib 80mg once daily.
- Suitable for a mandatory biopsy defined as having an accessible tumour and a stable
clinical condition that will allow the patient to tolerate the procedure. The biopsy
should be performed within 60 days prior to the planned first dose of study treatment.
- Patients must have measurable disease per Response Evaluation Criteria In Solid
Tumours (RECIST) 1.1.
- World Health Organisation (WHO) performance status 0 or 1 with no deterioration
between screening and the first dose of study treatment.
- A minimum life expectancy of 12 weeks.
- Ability to swallow and retain oral medication and have adequate venous access.
- Provision of archival tumour tissue for exploratory research (if such tissue/sample is
available, its provision is mandatory).
- Ability and willingness to comply with the study and follow-up.
- Adequate coagulation parameters, defined as: International Normalisation Ratio (INR)
<1.5 × upper limit of normal (ULN) and activated partial thromboplastin time <1.5 ×
ULN unless patients are receiving therapeutic anti-coagulation which affects these
- Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically
stable on low molecular weight heparin, factor Xa inhibitors or thrombin inhibitors
for ≥2 weeks.
- Willingness to adhere to the study treatment-specific contraception requirements.
Exclusion Criteria applicable to all study treatment modules (Groups A/B):
- Patients whose disease has progressed within the first 3 months of osimertinib
- Patients must not have experienced a toxicity(-ies) that led to permanent
discontinuation or dose reduction of prior osimertinib or have any unresolved
toxicities from prior osimertinib treatment greater than CTCAE (Common Terminology
Criteria for Adverse Event) Grade 1 at the time of starting study treatment
- Patients must not have discontinued osimertinib >60 days prior to the first dose of
- Prior or concurrent treatment with any systemic anticancer therapy for locally
advanced/metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or
any investigational drug (exceptions do apply)
- Major surgery within the 28 days prior to the first dose of study treatment except:
- After minor surgery, at least 7 postoperative days must elapse before study
treatment is initiated.
- After placement of vascular access, this waiting period is not required.
- Receipt of live attenuated vaccine within 30 days prior to the first dose of study
- Treatment with warfarin/coumarin analogues within 7 days prior to the first dose of
- Diagnosis of small cell lung cancer (SCLC) or squamous cell carcinoma (SCC)
- Spinal cord compression, symptomatic and unstable brain metastases, except for those
patients who have completed definitive therapy, are not on steroids, have a stable
neurologic status for at least 2 weeks after completion of the definitive therapy and
- Allogenic organ transplantation
- As judged by the investigator, any evidence of severe or uncontrolled systemic disease
or evidence of any other significant clinical disorder or laboratory finding that
makes it undesirable for the patient to participate in the study.
- History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease for at
least 2 years before the first dose of study treatment, and with low potential
risk for recurrence.
- Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of
- Adequately treated carcinoma in situ without evidence of disease.
- Localised non-invasive primary disease under surveillance.
- Active infection, including infections with hepatitis B virus, hepatitis C virus, or
human immunodeficiency virus (exceptions apply)
- Pregnancy or breastfeeding in female patients
- Any of the following cardiac criteria:
- Any clinically important abnormalities in rhythm, conduction, or morphology of
- Unstable atrial fibrillation or unstable cardiac arrhythmia with a ventricular
rate >100 bpm on an ECG at rest.
- Uncontrolled hypertension
- Uncontrolled angina or acute coronary syndrome within 6 months prior to
- At risk for brain perfusion problems or stroke, or transient ischemic attack in
the last 6 months prior to screening
- Symptomatic heart failure
- Prior or current cardiomyopathy.
- Severe valvular heart disease
- Inadequate bone marrow reserve or organ function
- Creatinine clearance <50 mL/min, calculated by Cockcroft-Gault equation