Phase 2 Platform Study in Participants with Advanced Non-Small Lung Cancer who progressed on First-Line Osimertinib Therapy (ORCHARD) - ORCHARD

Study identifier:D6186C00001

ClinicalTrials.gov identifier:NCT03944772

EudraCT identifier:2018-003974-29

CTIS identifier:2023-504624-25-00

Recruitment Complete

Official Title

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)

Medical condition

Non-small Cell Lung Cancer

Phase

Phase 2

Healthy volunteers

Study drug

Osimertinib, Savolitinib, Gefitinib, Necitumumab, Durvalumab, Carboplatin, Pemetrexed, Alectinib, Selpercatinib, Selumetinib, Etoposide, Cisplatin, Datopotamab deruxtecan

Sex

All

Actual Enrollment

247

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 25 Jun 2019

Primary Completion Date: 14 Apr 2025

Estimated Study Completion Date: 03 May 2028

Study design

Allocation: Non-randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Apr 2026 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

Inclusion criteria applicable to all study treatment modules (Group A and B)
1. Non-small-cell lung cancer (NSCLC) with the following features:
(a) Locally advanced or metastatic disease (ie, advanced NSCLC) not amenable to curative surgery or radiotherapy at study entry.
(b) Histologically or cytologically confirmed adenocarcinoma of the lung (participants with mixed histology are eligible if adenocarcinoma is the predominant histology) harboring EGFR mutation(s) known to be associated with EGFR tyrosine kinase inhibitors (TKI) sensitivity at diagnosis. Any histologically identifiable component of neuroendocrine transformation to small-cell lung cancer (SCLC) or large cell NEC is required for treatment under Module 7.
(c) 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, participants 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).
Participants previously treated adjuvantly or neo-adjuvantly are eligible per Exclusion Criterion 5.
(d) 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 participant to tolerate the procedure. The biopsy should be performed within 60 days of the planned first dose of study treatment.
3. Participants must have measurable disease per RECIST v1.1, 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 v1.1. 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 participants are receiving therapeutic anti-coagulation which affects these parameters.
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Exclusion Criteria applicable to all study treatment modules (Groups A/B):
1. Participants whose disease has progressed within the first 3 months of osimertinib treatment (refractory to osimertinib treatment).
2. Participants must not have experienced a toxicity(-ies) that led to permanent discontinuation or dose reduction of prior osimertinib.
(a) Participants 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 common terminology criteria for adverse events (CTCAE) Grade 1 at the time of starting study treatment.
4. Participants should not have discontinued osimertinib > 60 days prior to the first dose of study treatment.
5. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
a) Absolute neutrophil count < 1.5 × 10^9/L.
b) Platelet count < 100 × 10^9/L.
c) Haemoglobin < 9 g/dL.
d) Alanine transaminase (ALT) > 2.5 × ULN.
e) Aspartate aminotransferase (AST) > 2.5 × ULN.
f) 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 Study Physician.

No locations available

Arms	Assigned Interventions
Experimental: Module 1: Osimertinib 80 mg + Savolitinib 600 mg or 300 mg Participants in the biomarker-matched group (Group A) who had hepatocyte growth factor receptor (MET) amplification and/or a MET exon 14 skipping mutation and had experienced disease progression on prior osimertinib monotherapy will receive oral osimertinib 80 mg tablet once daily (QD) in combination with oral savolitinib 600 mg (3 × 200 mg) or 300 mg (3 × 100 mg; for participants weighing ≤ 55 kg at screening and for all Japanese participants) tablets QD until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met. After protocol amendment 3, participants will receive oral savolitinib 300 mg flat dose QD, irrespective of weight at screening or ethnicity. Participants who commenced study treatment at 600 mg savolitinib either continued at 600 mg dose or changed to 300 mg.	Drug: Osimertinib Participants will receive oral osimertinib tablets as stated in arm description. Other Name: TAGRISSO Drug: Savolitinib Participants will receive oral savolitinib tablets as stated in the arm description.
Experimental: Module 2: Osimertinib 80 mg + Gefitinib 250 mg Participants in the biomarker-matched group (Group A) with a mutation at C797 residue in the epidermal growth factor (EGFR) receptor and had experienced disease progression on prior osimertinib monotherapy will receive oral osimertinib 80 mg tablet QD in combination with oral gefitinib 250 mg tablet QD until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.	Drug: Osimertinib Participants will receive oral osimertinib tablets as stated in arm description. Other Name: TAGRISSO Drug: Gefitinib Participants will receive oral gefitinib tablets as stated in the arm description. Other Name: Iressa
Experimental: Module 3: Osimertinib 80 mg + Necitumumab 800 mg Participants in the biomarker-matched group (Group A) who had epidermal growth factor receptor (EGFR) amplification and/or a mutation at L718 residue in EGFR and had experienced disease progression on prior osimertinib monotherapy will receive oral osimertinib 80 mg tablet QD in combination with IV necitumumab infusion 800 mg QD on Days 1 and 8 of each 3-week cycle until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.	Drug: Osimertinib Participants will receive oral osimertinib tablets as stated in arm description. Other Name: TAGRISSO Drug: Necitumumab Participants will receive IV infusion of necitumumab as stated in the arm description. Other Name: Portrazza
Experimental: Module 4: Pemetrexed 500 mg/m^2 + Carboplatin AUC 5 + Durvalumab 1500 mg Participants in the biomarker non-matched group (Group B) who had experienced disease progression on prior osimertinib monotherapy will receive IV durvalumab 1500 mg along with platinum-containing doublet therapy (IV pemetrexed 500 mg/m^2 of body surface area [BSA] and IV carboplatin area under the concentration-time curve [AUC] 5) on Day 1 of every 21-day cycle for up to 6 cycles. Following doublet chemotherapy, participants whose disease has not progressed will continue to receive IV pemetrexed 500 mg/m^2 maintenance therapy and IV durvalumab 1500 mg on Day 1 of every 28-day cycle until disease progression or unacceptable toxicity.	Drug: Durvalumab Participants will receive IV infusion of durvalumab as stated in the arm description. Other Name: IMFINZI Drug: Carboplatin Participants will receive IV infusion of carboplatin as stated in the arm description. Drug: Pemetrexed Participants will receive IV infusion of pemetrexed as stated in the arm description.
Experimental: Module 5: Osimertinib 80 mg + Alectinib 600 mg Participants in the biomarker-matched group (Group A) who had anaplastic lymphoma kinase (ALK) rearrangement and had experienced disease progression on prior osimertinib monotherapy will receive oral osimertinib 80 mg tablet QD in combination with oral alectinib 600 mg (4 × 150 mg) capsule twice daily (BID) until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.	Drug: Osimertinib Participants will receive oral osimertinib tablets as stated in arm description. Other Name: TAGRISSO Drug: Alectinib Participants will receive oral alectinib capsules as stated in the arm description. Other Name: Alecensa
Experimental: Module 6: Osimertinib 80 mg + Selpercatinib 160 mg Participants in the biomarker-matched group (Group A) who had rearranged during transfection (RET) rearrangement and had experienced disease progression on prior osimertinib monotherapy will receive oral osimertinib 80 mg tablet QD in combination with oral selpercatinib 160 mg (2 × 80 mg capsule BID or 4 × 40 mg capsule BID) until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.	Drug: Osimertinib Participants will receive oral osimertinib tablets as stated in arm description. Other Name: TAGRISSO Drug: Selpercatinib Participants will receive oral selpercatinib capsules as stated in the arm description. Other Name: Loxo-292, Retevmo, Retsevmo
Experimental: Module 7: Etoposide 80-100mg/m^2 + Cisplatin 75-80mg/m^2 /Carboplatin AUC 5-6 + Durvalumab 1500mg Participants in the biomarker-matched group (Group A) who had neuroendocrine transformation to small cell lung cancer (tSCLC) or large cell neuroendocrine carcinoma (NEC) and had experienced disease progression on prior osimertinib monotherapy will receive IV durvalumab 1500 mg on Day 1 in combination with IV etoposide 80-100 mg/m^2 on Days 1, 2 and 3 and IV cisplatin 75-80 mg/m^2 or carboplatin AUC 5 to 6 (as appropriate) on Day 1 of every 21-day cycle for up to 4 cycles. Following etoposide and platinum therapy, participants whose disease has not progressed continued to receive durvalumab on Day 1 of every 28-day cycle until disease progression or unacceptable toxicity.	Drug: Durvalumab Participants will receive IV infusion of durvalumab as stated in the arm description. Other Name: IMFINZI Drug: Carboplatin Participants will receive IV infusion of carboplatin as stated in the arm description. Drug: Etoposide Participants will receive IV infusion of etoposide as stated in the arm description. Drug: Cisplatin Participants will receive IV infusion of cisplatin as stated in the arm description.
Experimental: Module 8: Osimertinib 80mg + Pemetrexed 500 mg/m^2 + Carboplatin AUC 5/Cisplatin 75 mg/m^2 Participants in the biomarker non-matched group (Group B) with advanced non-small cell lung cancer (NSCLC) harbouring an EGFR-sensitising mutation and not amenable to surgery or radiotherapy who had experienced disease progression on prior osimertinib monotherapy will receive oral osimertinib 80 mg tablet QD in combination with platinum-containing doublet therapy (IV pemetrexed 500 mg/m^2 of BSA, carboplatin AUC 5 or cisplatin 75 mg/m^2 QD on Day 1 of every 21-day cycle for 4 weeks). Following 4 cycles of doublet chemotherapy, the participants who will not progress, will receive IV pemetrexed 500 mg/m^2 of BSA maintenance therapy on Day 1 of every 21-day cycle and oral osimertinib 80 mg tablet QD until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.	Drug: Osimertinib Participants will receive oral osimertinib tablets as stated in arm description. Other Name: TAGRISSO Drug: Carboplatin Participants will receive IV infusion of carboplatin as stated in the arm description. Drug: Pemetrexed Participants will receive IV infusion of pemetrexed as stated in the arm description. Drug: Cisplatin Participants will receive IV infusion of cisplatin as stated in the arm description.
Experimental: Module 9: Osimertinib 80 mg + Selumetinib 75 mg Participants in the biomarker-matched group (Group A) who had EGFRm+ NSCLC harbouring BRAF fusions and/or BRAF V600E mutation and had experienced disease progression on prior osimertinib monotherapy will receive oral osimertinib 80 mg tablet QD in combination with oral selumetinib 75 mg (3 × 25 mg) capsule BID (4 days on and 3 days off treatment; not exceeding 150 mg/day), until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.	Drug: Osimertinib Participants will receive oral osimertinib tablets as stated in arm description. Other Name: TAGRISSO Drug: Selumetinib Participants will receive oral selumetinib capsules as stated in the arm description. Other Name: Koselugo
Experimental: Module 10 Cohort 1: Osimertinib 80 mg + Datopotamab deruxtecan 4.0 mg/kg Participants in the biomarker non-matched group (Group B) with EGFR+ NSCLC who had experienced disease progression on prior osimertinib monotherapy will receive oral osimertinib 80 mg tablet QD in combination with IV datopotamab deruxtecan (Dato-DXd) infusion 4.0 mg/kg on Day 1 of every 3-week cycle until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.	Drug: Osimertinib Participants will receive oral osimertinib tablets as stated in arm description. Other Name: TAGRISSO Drug: Datopotamab deruxtecan Participants will receive IV infusion of datopotamab deruxtecan as stated in the arm description. Other Name: DS 1062a Other Name: Datroway
Experimental: Module 10 Cohort 2: Osimertinib 80 mg + Datopotamab deruxtecan 6.0 mg/kg Participants in the biomarker non-matched group (Group B) with EGFR+ NSCLC who had experienced disease progression on prior osimertinib monotherapy will receive oral osimertinib 80 mg tablet QD in combination with IV datopotamab deruxtecan (Dato-DXd) 6.0 mg/kg on Day 1 of every 3-week cycle until disease progression, unacceptable toxicity, withdrawal of participant consent, or another discontinuation criterion was met.	Drug: Osimertinib Participants will receive oral osimertinib tablets as stated in arm description. Other Name: TAGRISSO Drug: Datopotamab deruxtecan Participants will receive IV infusion of datopotamab deruxtecan as stated in the arm description. Other Name: DS 1062a Other Name: Datroway

Documents available

ORCHARD study design article. The article includes Module 5 and Module 6 but was written prior to the subsequent modules being added.
Download
Redacted CSR Synopsis
Download
Redacted SAP
Download
Redacted CSP
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

[email protected]

Contact Backup

Cancer Study Locator (For US sites only)

1-877-400-4656

[email protected]

Investigators

Principal Investigator

Helena A Yu

Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA