Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Who Progressed on First-Line Osimertinib Therapy (ORCHARD)

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Osimertinib
* Drug: Savolitinib
* Drug: Gefitinib
* Drug: Necitumumab
* Drug: Durvalumab
* Drug: Carboplatin
* Drug: Pemetrexed
* Drug: Alectinib
* Drug: Selpercatinib
* Drug: Selumetinib
* Drug: Etoposide
* Drug: Cisplatin
* Drug: Datopotamab deruxtecan


Participation Criteria
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Eligibility Criteria
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Inclusion criteria applicable to all study treatment modules (Group A & B) NSCLC with the following features: Locally advanced or metastatic disease (ie, advanced NSCLC) not amenable to curative surgery or radiotherapy at study entry. 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. 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. Evidence of radiological disease progression on first-line monotherapy with osimertinib 80 mg po QD. 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. 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. 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): Patients whose disease has progressed within the first 3 months of osimertinib treatment (refractory to osimertinib treatment). 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. Any unresolved toxicities from prior osimertinib treatment greater than CTCAE 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. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: Absolute neutrophil count < 1.5 × 109/L. Platelet count < 100 × 109/L. Haemoglobin < 9 g/dL. Alanine transaminase (ALT) > 2.5 × ULN. Aspartate aminotransferase (AST) > 2.5 × ULN. Total bilirubin (TBL) > 1.5 × ULN, or > 3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia). 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 Study Physician.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Module 1: Osimertinib + Savolitinib<br>The patients in this group will receive osimertinib taken in combination with savolitinib | Drug: Osimertinib<br>* Osimertinib given orally at 80 mg once daily<br>* Other names: TAGRISSO;Drug: Savolitinib<br>* Savolitinib will be given orally at 300 mg or 600mg once daily<br>|
| Experimental: Module 2: Osimertinib + Gefitinib<br>The patients in this group will receive osimertinib taken in combination with gefitinib | Drug: Osimertinib<br>* Osimertinib given orally at 80 mg once daily<br>* Other names: TAGRISSO;Drug: Gefitinib<br>* Gefitinib given orally at 250 mg once daily<br>* Other names: Iressa;|
| Experimental: Module 3: Osimertinib + Necitumumab<br>The patients in this group will receive osimertinib taken in combination with necitumumab | Drug: Osimertinib<br>* Osimertinib given orally at 80 mg once daily<br>* Other names: TAGRISSO;Drug: Necitumumab<br>* Necitumumab given IV at 800 mg on Day 1 and Day 8 of every 3-week cycle<br>* Other names: Portrazza;|
| Experimental: Module 4: Carboplatin + Pemetrexed + Durvalumab)<br>The patients in this group will receive platinum-containing doublet (carboplatin + pemetrexed) taken in combination with durvalumab. | Drug: Durvalumab<br>* Durvalumab given IV at 1500 mg on Day 1 of every cycle<br>* Other names: IMFINZI;Drug: Carboplatin<br>* Carboplatin given IV on Day 1 of every 21-day cycle for up to 6 cycles<br>Drug: Pemetrexed<br>* Pemetrexed given IV at 500 mg/m2 body BSA on Day 1 of every cycle<br>|
| No Intervention: Observational Cohort: No study drug<br>Patients in this group will not receive study treatment but receive further anticancer care (Standard of Care therapy or other experimental therapies) or supportive care, as clinically indicated, in accordance with local practice. With Group C, the aim is to understand the clinical course and/or outcome for the overall clinical population after progression on first-line monotherapy with osimertinib. | |
| Experimental: Module 5: Osimertinib + Alectinib<br>The patients in this group will receive osimertinib taken in combination with alectinib | Drug: Osimertinib<br>* Osimertinib given orally at 80 mg once daily<br>* Other names: TAGRISSO;Drug: Alectinib<br>* Alectinib given orally at 600mg twice daily and for Japanese patients at 300mg twice daily.<br>* Other names: Alecensa;|
| Experimental: Module 6: Osimertinib + Selpercatinib<br>The patients in this group will receive osimertinib taken in combination with selpercatinib | Drug: Osimertinib<br>* Osimertinib given orally at 80 mg once daily<br>* Other names: TAGRISSO;Drug: Selpercatinib<br>* Selpercatinib given orally at 160mg twice daily<br>* Other names: Loxo-292, Retevmo, Retsevmo;|
| Experimental: Module 7: Etoposide + Durvalumab + Carboplatin or Cisplatin<br>The patients in this group will receive platinum-containing doublet (etoposide + carboplatin or cisplatin) taken in combination with durvalumab. | Drug: Durvalumab<br>* Durvalumab given IV at 1500 mg on Day 1 of every cycle<br>* Other names: IMFINZI;Drug: Carboplatin<br>* Carboplatin given IV on Day 1 of every 21-day cycle for up to 6 cycles<br>Drug: Etoposide<br>* Etoposide 80-100 mg/m2 given IV on day 1, 2 and 3 of every 21-day cycle for up to 4 cycles.<br>Drug: Cisplatin<br>* Cisplatin 75-80 mg/m2 given IV on days 1 of each cycle<br>|
| Experimental: Module 8: Osimertinib + Pemetrexed + Carboplatin or Cisplatin.<br>The patients in this group will receive Osimertinib plus platinum-containing doublet (pemetrexed + carboplatin or cisplatin). | Drug: Osimertinib<br>* Osimertinib given orally at 80 mg once daily<br>* Other names: TAGRISSO;Drug: Carboplatin<br>* Carboplatin given IV on Day 1 of every 21-day cycle for up to 6 cycles<br>Drug: Pemetrexed<br>* Pemetrexed given IV at 500 mg/m2 body BSA on Day 1 of every cycle<br>Drug: Cisplatin<br>* Cisplatin 75-80 mg/m2 given IV on days 1 of each cycle<br>|
| Experimental: Module 9: Osimertinib + Selumetinib<br>The patients in this group will receive osimertinib taken in combination with selumetinib | Drug: Osimertinib<br>* Osimertinib given orally at 80 mg once daily<br>* Other names: TAGRISSO;Drug: Selumetinib<br>* Selumetinib given orally at 75 mg twice daily for 4 days, followed by 3 days off treatment<br>* Other names: Koselugo;|
| Experimental: Module 10: Osimertinib + datopotamab deruxtecan<br>The patients in this group will receive osimertinib taken in combination with datopotamab deruxtecan. | Drug: Osimertinib<br>* Osimertinib given orally at 80 mg once daily<br>* Other names: TAGRISSO;Drug: Datopotamab deruxtecan<br>* Datopotamab deruxtecan given IV at 4 or 6 mg/kg on Day 1 of every 3-week cycle.<br>* Other names: DS 1062a;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | 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). | Measured from first dose until confirmed response or progression. For each patient this is expected to be 3 months on average | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | 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). | Measured from first dose until progression. For each patient this is expected to be 6 months on average | 
| Duration of response (DoR) | 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). | Measured from response until progression. For each patient this is expected to be 6 months on average | 
| Overall survival (OS) | The time from the date of the first dose of study treatment until death due to any cause. | Measured from first dose until death or final cohort data cut-off. For each patient this is expected to be 20 months on average | 
| Plasma concentrations of therapeutic agents | Blood samples will be collected at various timepoints to evaluate the sparse pharmacokinetics of study 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). | 
| Plasma concentrations of therapeutic agents | Blood samples will be collected at various timepoints to evaluate the serial pharmacokinetics of study therapeutic agents | Pre-dose and serial post-dose blood samples (1 hour, 2 hours, 4 hours, 6 hours, 8 hours) on Day 15 of Cycle 1 for alectinib and selpercatinib only. | 
| 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 | To evaluate safety and tolerability of each study treatment | Continuously from first dose to end of safety follow up after study treatment discontinuation (approximately up to 21 Months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tSCLC, NSCLC, Non-small cell lung cancer, 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