Non-Small Cell Lung Cancer
Conditions
Keywords
Non-small cell lung cancer, NSCLC, tSCLC, NEC, Phase II, Platform study, Biomarker-directed, Durvalumab, Osimertinib, Savolitinib, Selumetinib, Etoposide, Gefitinib, Necitumumab, Platinum-containing doublet, Pemetrexed, EGFR positive, Carboplatin, Alectinib, Selpercatinib, Cisplatin, TKI-resistant, MET amplification, MET exon 14 skipping, EGFR, EGFR C797X, EGFR G724X, EGFR L718X, EGFR exon 20 insertion, EGFR amplification, BRAF V600E, ALK rearrangement, RET rearrangement, ROS1 rearrangement, NTRK fusion, KRAS G12C, Datopotamab deruxtecan
Brief summary
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.
Detailed description
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.
Interventions
DRUGOsimertinib
Osimertinib given orally at 80 mg once daily
DRUGSavolitinib
Savolitinib will be given orally at 300 mg or 600mg once daily
DRUGGefitinib
Gefitinib given orally at 250 mg once daily
DRUGNecitumumab
Necitumumab given IV at 800 mg on Day 1 and Day 8 of every 3-week cycle
DRUGDurvalumab
Durvalumab given IV at 1500 mg on Day 1 of every cycle
DRUGCarboplatin
Carboplatin given IV on Day 1 of every 21-day cycle for up to 6 cycles
DRUGPemetrexed
Pemetrexed given IV at 500 mg/m2 body BSA on Day 1 of every cycle
DRUGAlectinib
Alectinib given orally at 600mg twice daily and for Japanese patients at 300mg twice daily.
DRUGSelpercatinib
Selpercatinib given orally at 160mg twice daily
DRUGSelumetinib
Selumetinib given orally at 75 mg twice daily for 4 days, followed by 3 days off treatment
DRUGEtoposide
Etoposide 80-100 mg/m2 given IV on day 1, 2 and 3 of every 21-day cycle for up to 4 cycles.
DRUGCisplatin
Cisplatin 75-80 mg/m2 given IV on days 1 of each cycle
DRUGDatopotamab deruxtecan
Datopotamab deruxtecan given IV at 4 or 6 mg/kg on Day 1 of every 3-week cycle.
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 2 platform study in patients with advanced Non-Small Lung Cancer harbouring an epidermal growth factor receptor (EGFR)-sensitizing mutation with evidence of radiological progression following first-Line osimertinib therapy. This study is modular in design, allowing evaluation of the efficacy, safety and tolerability of multiple study treatments. The study will be conducted in three groups (Groups A, B and C). Patient allocation to a study treatment within each group will be based on tumour molecular profile. Biomarker positive patients or patients with histologically identifiable neuroendocrine transformation to small cell lung cancer (SCLC) or large cell neuroendocrine carcinoma (NEC) will be allocated to a biomarker-matched study treatment in Group A, patients without a biomarker will be allocated to a study treatment in Group B and patients with a biomarker amenable to therapies not currently available in ORCHARD will be allocated to Group C.
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
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 7. 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 study treatment. 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. \-------------------------------------------------------------------------------------------
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR) | Measured from first dose until confirmed response or progression. For each patient this is expected to be 3 months on average | The percentage of patients with a confirmed investigator-assessed complete or partial response according to Response Evaluation Criteria In Solid Tumours (RECIST) 1.1. Patients will be followed up every 6 weeks (±1 week) for the first 24 weeks and every 9 weeks thereafter until RECIST 1.1 defined disease progression or cessation of study treatment (if treating beyond progression). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | Measured from first dose until progression. For each patient this is expected to be 6 months on average | The time from first dose until the date of objective disease progression or death (by any cause in the absence of progression). Patients will be followed up every 6 weeks (±1 week) for the first 24 weeks and every 9 weeks thereafter until RECIST (Response Evaluation Criteria In Solid Tumours)1.1 defined disease progression or cessation of study treatment (if treating beyond progression). |
| Duration of response (DoR) | Measured from response until progression. For each patient this is expected to be 6 months on average | The time from the date of first response until date of disease progression or death in the absence of disease progression. Patients will be followed up every 6 weeks (±1 week) for the first 24 weeks and every 9 weeks thereafter until RECIST 1.1 defined disease progression or cessation of study treatment (if treating beyond progression). |
| Overall survival (OS) | Measured from first dose until death or final cohort data cut-off. For each patient this is expected to be 20 months on average | The time from the date of the first dose of study treatment until death due to any cause. |
| Plasma/serum concentrations of therapeutic agents | Pre-dose and 1 hour post-dose blood samples on Day 1 of Cycles 1, 3 (Cycle 2 for durvalumab), 6 for all therapeutic agents and a sample at the 90-day safety follow up for durvalumab only. (One Cycle = 21 or 28 days, depending on treatment). | Blood samples will be collected at various timepoints to evaluate the sparse pharmacokinetics of study therapeutic agents. |
| Incidence of Treatment-emergent adverse events (AEs) and serious adverse events (SAEs) as characterized and graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event [CTCAE] v5 | Continuously from first dose to end of safety follow up after study treatment discontinuation (approximately up to 21 Months) | To evaluate safety and tolerability of each study treatment |
Countries
Denmark, Italy, Japan, Netherlands, Norway, South Korea, Spain, Sweden, United States
Outcome results
None listed