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

• ClinicalTrials.gov Identifier: NCT03944772
• Recruitment Status: Active, not recruiting
• First Posted: May 10, 2019
• Last Update Posted: April 15, 2024
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Non-Small Cell Lung Cancer	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	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 248 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• 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.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Biomarker-directed Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy.
• Actual Study Start Date: June 25, 2019
• Estimated Primary Completion Date: May 6, 2025
• Estimated Study Completion Date: May 6, 2025

Arms and Interventions

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 Name: 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 Name: TAGRISSO; Drug: Gefitinib; Gefitinib given orally at 250 mg once daily; Other Name: 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 Name: TAGRISSO; Drug: Necitumumab; Necitumumab given IV at 800 mg on Day 1 and Day 8 of every 3-week cycle; Other Name: 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 Name: 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 Name: TAGRISSO; Drug: Alectinib; Alectinib given orally at 600mg twice daily and for Japanese patients at 300mg twice daily.; Other Name: 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 Name: TAGRISSO; Drug: Selpercatinib; Selpercatinib given orally at 160mg twice daily; Other Name: 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 Name: 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 Name: 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 Name: TAGRISSO; Drug: Selumetinib; Selumetinib given orally at 75 mg twice daily for 4 days, followed by 3 days off treatment; Other Name: 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 Name: TAGRISSO; Drug: Datopotamab deruxtecan; Datopotamab deruxtecan given IV at 4 or 6 mg/kg on Day 1 of every 3-week cycle.; Other Name: DS 1062a

Outcome Measures

Primary Outcome Measures :

1. Objective response rate (ORR) [ Time Frame: 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 Outcome Measures :

1. Progression-free survival (PFS) [ Time Frame: 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).
2. Duration of response (DoR) [ Time Frame: 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).
3. Overall survival (OS) [ Time Frame: 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.
4. Plasma concentrations of therapeutic agents [ Time Frame: 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.
5. Plasma concentrations of therapeutic agents [ Time Frame: 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. ]
   Blood samples will be collected at various timepoints to evaluate the serial pharmacokinetics of study therapeutic agents
6. 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 [ Time Frame: 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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, California

Research Site

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

United States, Connecticut

Research Site

New Haven, Connecticut, United States, 06510

United States, Illinois

Research Site

Chicago, Illinois, United States, 60612

United States, Maryland

Research Site

Baltimore, Maryland, United States, 21224

United States, Massachusetts

Research Site

Boston, Massachusetts, United States, 02114

Research Site

Boston, Massachusetts, United States, 02215

United States, Michigan

Research Site

Grand Rapids, Michigan, United States, 49503

United States, New York

Research Site

New York, New York, United States, 10017

Research Site

New York, New York, United States, 10032

United States, Oregon

Research Site

Portland, Oregon, United States, 97239

United States, Pennsylvania

Research Site

Pittsburgh, Pennsylvania, United States, 15232

United States, Texas

Research Site

Houston, Texas, United States, 77030

United States, Washington

Research Site

Seattle, Washington, United States, 98109

Denmark

Research Site

Odense C, Denmark, 5000

Italy

Research Site

Catania, Italy, 95123

Research Site

Napoli, Italy, 80131

Research Site

Orbassano, Italy, 10043

Research Site

Padova, Italy, 35128

Research Site

Varese, Italy, 21100

Japan

Research Site

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

Korea, Republic of

Research Site

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

Netherlands

Research Site

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

Norway

Research Site

Drammen, Norway, 3004

Research Site

Oslo, Norway, N-0310

Research Site

Trondheim, Norway, 7030

Spain

Research Site

A Coruña, Spain, 15006

Research Site

Barcelona, Spain, 08025

Research Site

Barcelona, Spain, 08036

Research Site

Madrid, Spain, 28041

Research Site

Madrid, Spain, 28046

Research Site

Sevilla, Spain, 41009

Sweden

Research Site

Stockholm, Sweden, 17176

Sponsors and Collaborators

AstraZeneca

Investigators

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

More Information

Additional Information:

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03944772
• Other Study ID Numbers: D6186C00001; 2018-003974-29 ( EudraCT Number )
• First Posted: May 10, 2019
• Last Update Posted: April 15, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• 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.
• 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.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:

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

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carboplatin; Etoposide; Pemetrexed; Durvalumab; Gefitinib; Osimertinib; Necitumumab; Alectinib; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Antineoplastic Agents, Immunological; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors