A Biomarker-Directed Phase 2 Platform Study in Patients with Advanced Non-Small Cell Lung Cancer whose Disease has Progressed on First-Line Osimertinib Therapy (ORCHARD)
Phase 2 Platform Study in Patients with Advanced Non-Small Lung Cancer who progressed on
First-Line Osimertinib Therapy. 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 (Group A & B)
1. NSCLC with the following features:
1. Locally advanced or metastatic disease (ie, advanced NSCLC) not amenable to
curative surgery or radiotherapy at study entry.
2. Histologically or cytologically confirmed adenocarcinoma of the lung (patients
with mixed histology are eligible if adenocarcinoma is the predominant histology)
harboring EGFR mutation(s) known to be associated with EGFR TKI sensitivity at
diagnosis. Any histologically identifiable component of neuroendocrine
transformation to SCLC or large cell NEC is required for treatment under Module
3. Received only one line of therapy, with single-agent osimertinib, for advanced
NSCLC, with clinical benefit as judged by investigator discretion.
(Note: a 'line' of therapy is defined as a daily anti-cancer treatment
administered for >14 days, or a single infusion of an intravenous anti-cancer
treatment. For instance, patients who have had <14 days of a first- or second-
generation TKI prior to osimertinib, and stopped due to adverse events, would be
eligible to enter this study, see also exclusion criteria 5).
Patients previously treated adjuvantly or neo-adjuvantly are eligible per
exclusion criterion 5.
4. Evidence of radiological disease progression on first-line monotherapy with
osimertinib 80 mg po QD.
2. Suitable for a mandatory biopsy defined as having an accessible tumor; by whichever
modality the site uses and, ideally, confirmed by the person who will perform the
procedure; and a stable clinical condition that will allow the patient to tolerate the
procedure. The biopsy should be performed within 60 days of the planned first dose of
3. Patients must have measurable disease per RECIST 1.1, as defined by at least 1 lesion
that can be accurately measured at baseline as ≥ 10 mm at the longest diameter (except
lymph nodes which must have a short axis ≥ 15 mm) with computed tomography (CT) or
magnetic resonance imaging (MRI), which is suitable for accurate repeated
measurements. Previously irradiated lesions or a lesion in the field of radiation
should not be used as measurable disease unless the lesion(s) has/have demonstrated
unequivocal disease progression by RECIST 1.1. Target lesions should not be used for
the baseline tumour biopsy, unless there are no other lesions suitable for biopsy and
they fulfil requirements.
4. 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 parameters.
Exclusion Criteria applicable to all study treatment modules (Groups A/B):
1. Patients whose disease has progressed within the first 3 months of osimertinib
treatment (refractory to osimertinib treatment).
2. Patients must not have experienced a toxicity(-ies) that led to permanent
discontinuation or dose reduction of prior osimertinib.
(a) Patients who had dose reductions in the past, but were receiving a full dose of
osimertinib at the time of pre-screening should be discussed with the Study Physician.
3. Any unresolved toxicities from prior osimertinib treatment greater than CTCAE Grade 1
at the time of starting study treatment.
4. Patients should not have discontinued osimertinib >60 days prior to the first dose of
5. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:
1. Absolute neutrophil count < 1.5 × 109/L.
2. Platelet count < 100 × 109/L.
3. Haemoglobin < 9 g/dL.
4. Alanine transaminase (ALT) > 2.5 × ULN.
5. Aspartate aminotransferase (AST) > 2.5 × ULN.
6. Total bilirubin (TBL) > 1.5 × ULN, or > 3 × ULN in the presence of documented
Gilbert's Syndrome (unconjugated hyperbilirubinaemia).
6. Creatinine clearance (CrCl) < 50 mL/min, calculated using Cockcroft-Gault equation
(Cockcroft and Gault 1976) or 24-hour urine collection. For medical conditions where
the Cockcroft-Gault equation is inappropriate or 24-hour urine collection is
unfeasible, CrCl may be calculated differently following written approval from the