A Biomarker-directed Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy

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 EGFR mutation(s) known to be associated with epidermal growth factor receptor (EGFR) 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 and a minimum life expectancy of 12 weeks.
• Adequate coagulation parameters, defined as: International Normalisation Ratio (INR) <1.5 × ULN and activated partial thromboplastin time <1.5 × ULN unless patients are receiving therapeutic anti-coagulation which affects these parameters.
• 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 treatment
• 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 should not have discontinued osimertinib >60 days prior to the first dose of study treatment
• Prior or concurrent treatment with any systemic anti-cancer 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:

  o 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.
• Treatment with warfarin/coumarin analogues within 7 days prior to the first dose of study treatment
• 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 steroids.
• Allogenic organ transplantation
• 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.
  • Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease
  • 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
• Pregnancy or breastfeeding in female patients
• Any of the following cardiac criteria:
  • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG
  • 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 screening.
  • 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