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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Osimertinib; Drug: Savolitinib; Drug: Gefitinib; Drug: Necitumumab; Drug: Durvalumab; Drug: Carboplatin; Drug: Pemetrexed; Drug: Alectinib; Drug: Selpercatinib; Drug: Etoposide; Drug: Cisplatin; Drug: Selumetinib; Drug: Datopotamab deruxtecan

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.

• Study Type: Interventional
• Enrollment (Actual): 248
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Cancer Study Locator (For US sites only); Phone Number: 1-877-400-4656; Email: astrazeneca@emergingmed.com
• Study Contact Backup: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Denmark
  • Odense C, Denmark, 5000
    • Research Site
• Italy
  • Catania, Italy, 95123
    • Research Site
  • Napoli, Italy, 80131
    • Research Site
  • Orbassano, Italy, 10043
    • Research Site
  • Padova, Italy, 35128
    • Research Site
  • Varese, Italy, 21100
    • Research Site
• Japan
  • Chuo-ku, Japan, 104-0045
    • Research Site
  • Fukuoka-shi, Japan, 812-8582
    • Research Site
  • Koto-ku, Japan, 135-8550
    • Research Site
  • Nagoya-shi, Japan, 464-8681
    • Research Site
  • Osaka-shi, Japan, 541-8567
    • Research Site
  • Wakayama-shi, Japan, 641-8510
    • Research Site
• Korea, Republic of
  • Seongnam-si, Korea, Republic of, 13620
    • Research Site
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 05505
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Research Site
  • Amsterdam, Netherlands, 1081 HV
    • Research Site
  • Maastricht, Netherlands, 6229 HX
    • Research Site
  • Nijmegen, Netherlands, 6525 GA
    • Research Site
  • Rotterdam, Netherlands, 3015GD
    • Research Site
• Norway
  • Drammen, Norway, 3004
    • Research Site
  • Oslo, Norway, N-0310
    • Research Site
  • Trondheim, Norway, 7030
    • Research Site
• Spain
  • A Coruña, Spain, 15006
    • Research Site
  • Barcelona, Spain, 08036
    • Research Site
  • Barcelona, Spain, 08025
    • Research Site
  • Madrid, Spain, 28046
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • Sevilla, Spain, 41009
    • Research Site
• Sweden
  • Stockholm, Sweden, 17176
    • Research Site
• United States
  • California
    • Duarte, California, United States, 91010
      • Research Site
    • Los Angeles, California, United States, 90048
      • Research Site
    • Sacramento, California, United States, 95817
      • Research Site
    • Santa Monica, California, United States, 90404
      • Research Site
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Research Site
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Research Site
  • New York
    • New York, New York, United States, 10032
      • Research Site
    • New York, New York, United States, 10017
      • Research Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Research Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98109
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

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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 study treatment.

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 Study Physician.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Module 1: Osimertinib + Savolitinib; The patients in this group will receive osimertinib taken in combination with savolitinib	Drug: Osimertinib; Osimertinib given orally at 80 mg once daily; Other Names: TAGRISSO; Drug: Savolitinib; Savolitinib will be given orally at 300 mg or 600mg once daily
Experimental: Module 2: Osimertinib + Gefitinib; The patients in this group will receive osimertinib taken in combination with gefitinib	Drug: Osimertinib; Osimertinib given orally at 80 mg once daily; Other Names: TAGRISSO; Drug: Gefitinib; Gefitinib given orally at 250 mg once daily; Other Names: Iressa
Experimental: Module 3: Osimertinib + Necitumumab; The patients in this group will receive osimertinib taken in combination with necitumumab	Drug: Osimertinib; Osimertinib given orally at 80 mg once daily; Other Names: TAGRISSO; Drug: Necitumumab; Necitumumab given IV at 800 mg on Day 1 and Day 8 of every 3-week cycle; Other Names: Portrazza
Experimental: Module 4: Carboplatin + Pemetrexed + Durvalumab); The patients in this group will receive platinum-containing doublet (carboplatin + pemetrexed) taken in combination with durvalumab.	Drug: Durvalumab; Durvalumab given IV at 1500 mg on Day 1 of every cycle; Other Names: IMFINZI; Drug: Carboplatin; Carboplatin given IV on Day 1 of every 21-day cycle for up to 6 cycles; Drug: Pemetrexed; Pemetrexed given IV at 500 mg/m2 body BSA on Day 1 of every cycle
No Intervention: Observational Cohort: No study drug; 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; The patients in this group will receive osimertinib taken in combination with alectinib	Drug: Osimertinib; Osimertinib given orally at 80 mg once daily; Other Names: TAGRISSO; Drug: Alectinib; Alectinib given orally at 600mg twice daily and for Japanese patients at 300mg twice daily.; Other Names: Alecensa
Experimental: Module 6: Osimertinib + Selpercatinib; The patients in this group will receive osimertinib taken in combination with selpercatinib	Drug: Osimertinib; Osimertinib given orally at 80 mg once daily; Other Names: TAGRISSO; Drug: Selpercatinib; Selpercatinib given orally at 160mg twice daily; Other Names: Loxo-292, Retevmo, Retsevmo
Experimental: Module 7: Etoposide + Durvalumab + Carboplatin or Cisplatin; The patients in this group will receive platinum-containing doublet (etoposide + carboplatin or cisplatin) taken in combination with durvalumab.	Drug: Durvalumab; Durvalumab given IV at 1500 mg on Day 1 of every cycle; Other Names: IMFINZI; Drug: Carboplatin; Carboplatin given IV on Day 1 of every 21-day cycle for up to 6 cycles; Drug: Etoposide; Etoposide 80-100 mg/m2 given IV on day 1, 2 and 3 of every 21-day cycle for up to 4 cycles.; Drug: Cisplatin; Cisplatin 75-80 mg/m2 given IV on days 1 of each cycle
Experimental: Module 8: Osimertinib + Pemetrexed + Carboplatin or Cisplatin.; The patients in this group will receive Osimertinib plus platinum-containing doublet (pemetrexed + carboplatin or cisplatin).	Drug: Osimertinib; Osimertinib given orally at 80 mg once daily; Other Names: TAGRISSO; Drug: Carboplatin; Carboplatin given IV on Day 1 of every 21-day cycle for up to 6 cycles; Drug: Pemetrexed; Pemetrexed given IV at 500 mg/m2 body BSA on Day 1 of every cycle; Drug: Cisplatin; Cisplatin 75-80 mg/m2 given IV on days 1 of each cycle
Experimental: Module 9: Osimertinib + Selumetinib; The patients in this group will receive osimertinib taken in combination with selumetinib	Drug: Osimertinib; Osimertinib given orally at 80 mg once daily; Other Names: TAGRISSO; Drug: Selumetinib; Selumetinib given orally at 75 mg twice daily for 4 days, followed by 3 days off treatment; Other Names: Koselugo
Experimental: Module 10: Osimertinib + datopotamab deruxtecan; The patients in this group will receive osimertinib taken in combination with datopotamab deruxtecan.	Drug: Osimertinib; Osimertinib given orally at 80 mg once daily; Other Names: TAGRISSO; Drug: Datopotamab deruxtecan; Datopotamab deruxtecan given IV at 4 or 6 mg/kg on Day 1 of every 3-week cycle.; Other Names: DS 1062a

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Helena A Yu, MD, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA

Publications and helpful links

General Publications

• Yu HA, Goldberg SB, Le X, Piotrowska Z, Goldman JW, De Langen AJ, Okamoto I, Cho BC, Smith P, Mensi I, Ambrose H, Kraljevic S, Maidment J, Chmielecki J, Li-Sucholeiki X, Doughton G, Patel G, Jewsbury P, Szekeres P, Riess JW. Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD). Clin Lung Cancer. 2021 Nov;22(6):601-606. doi: 10.1016/j.cllc.2021.06.006. Epub 2021 Jun 25.
• Schmid S, Fruh M, Peters S. Targeting MET in EGFR resistance in non-small-cell lung cancer-ready for daily practice? Lancet Oncol. 2020 Mar;21(3):320-322. doi: 10.1016/S1470-2045(19)30859-9. Epub 2020 Feb 3. No abstract available.

Helpful Links

• ORCHARD study design article. The article includes Module 5 and Module 6 but was written prior to the subsequent modules being added.

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2019
• Primary Completion (Estimated): May 6, 2025
• Study Completion (Estimated): May 6, 2025

Study Registration Dates

• First Submitted: April 29, 2019
• First Submitted That Met QC Criteria: May 8, 2019
• First Posted (Actual): May 10, 2019

Study Record Updates

• Last Update Posted (Estimated): April 15, 2024
• Last Update Submitted That Met QC Criteria: April 12, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: NSCLC; Cisplatin; Non-small cell lung cancer; EGFR; Osimertinib; Savolitinib; Carboplatin; Etoposide; Pemetrexed; KRAS G12C; MET amplification; Phase II; Durvalumab; MET exon 14 skipping; BRAF V600E; Gefitinib; NEC; Platform study; Selumetinib; EGFR amplification; Alectinib; tSCLC; Biomarker-directed; Necitumumab; Platinum-containing doublet; EGFR positive; Selpercatinib; TKI-resistant; EGFR C797X; EGFR G724X; EGFR L718X; EGFR exon 20 insertion; ALK rearrangement; RET rearrangement; ROS1 rearrangement; NTRK fusion; Datopotamab deruxtecan
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Folic Acid Antagonists; Tyrosine Kinase Inhibitors; Carboplatin; Etoposide; Durvalumab; Gefitinib; Osimertinib; Necitumumab; Pemetrexed; Alectinib
• Other Study ID Numbers: D6186C00001; 2018-003974-29 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No