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: May 13, 2024
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: April 29, 2019
• First Posted Date: May 10, 2019
• Last Update Posted Date: May 13, 2024
• Actual Study Start Date: June 25, 2019
• Estimated Primary Completion Date: May 6, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 8, 2019)

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).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 24, 2020)

• 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).
• 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).
• 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.
• 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.
• 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
• 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

Original Secondary Outcome Measures (submitted: May 8, 2019)

• Progression-free survival (PFS) [ Time Frame: Measured from first dose until progression. For each patient this is expected to be 18 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) [ Time Frame: Measured from response until progression. For each patient this is expected to be 15 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) [ Time Frame: Measured from first dose until death or final cohort data cut-off. For each patient this is expected to be 30 months on average ]
  The time from the date of the first dose of study treatment until death due to any cause.
• Plasma concentrations of therapeutic agents [ Time Frame: Pre-dose and 1 hour post-dose blood samples on Day 1 of Cycles 1, 3, 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 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 [ 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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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

• Condition: Non-Small Cell Lung Cancer

Intervention

• 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
• Drug: Gefitinib
  Gefitinib given orally at 250 mg once daily
  Other Name: Iressa
• Drug: Necitumumab
  Necitumumab given IV at 800 mg on Day 1 and Day 8 of every 3-week cycle
  Other Name: Portrazza
• 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
• Drug: Alectinib
  Alectinib given orally at 600mg twice daily and for Japanese patients at 300mg twice daily.
  Other Name: Alecensa
• Drug: Selpercatinib
  Selpercatinib given orally at 160mg twice daily
  Other Name: Loxo-292, Retevmo, Retsevmo
• Drug: Selumetinib
  Selumetinib given orally at 75 mg twice daily for 4 days, followed by 3 days off treatment
  Other Name: Koselugo
• 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
• 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

Study Arms

• Experimental: Module 1: Osimertinib + Savolitinib
  The patients in this group will receive osimertinib taken in combination with savolitinib
  Interventions:

  • Drug: Osimertinib
  • Drug: Savolitinib
• Experimental: Module 2: Osimertinib + Gefitinib
  The patients in this group will receive osimertinib taken in combination with gefitinib
  Interventions:

  • Drug: Osimertinib
  • Drug: Gefitinib
• Experimental: Module 3: Osimertinib + Necitumumab
  The patients in this group will receive osimertinib taken in combination with necitumumab
  Interventions:

  • Drug: Osimertinib
  • Drug: Necitumumab
• Experimental: Module 4: Carboplatin + Pemetrexed + Durvalumab)
  The patients in this group will receive platinum-containing doublet (carboplatin + pemetrexed) taken in combination with durvalumab.
  Interventions:

  • Drug: Durvalumab
  • Drug: Carboplatin
  • Drug: Pemetrexed
• 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
  Interventions:

  • Drug: Osimertinib
  • Drug: Alectinib
• Experimental: Module 6: Osimertinib + Selpercatinib
  The patients in this group will receive osimertinib taken in combination with selpercatinib
  Interventions:

  • Drug: Osimertinib
  • Drug: Selpercatinib
• 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.
  Interventions:

  • Drug: Durvalumab
  • Drug: Carboplatin
  • Drug: Etoposide
  • Drug: Cisplatin
• Experimental: Module 8: Osimertinib + Pemetrexed + Carboplatin or Cisplatin.
  The patients in this group will receive Osimertinib plus platinum-containing doublet (pemetrexed + carboplatin or cisplatin).
  Interventions:

  • Drug: Osimertinib
  • Drug: Carboplatin
  • Drug: Pemetrexed
  • Drug: Cisplatin
• Experimental: Module 9: Osimertinib + Selumetinib
  The patients in this group will receive osimertinib taken in combination with selumetinib
  Interventions:

  • Drug: Osimertinib
  • Drug: Selumetinib
• Experimental: Module 10: Osimertinib + datopotamab deruxtecan
  The patients in this group will receive osimertinib taken in combination with datopotamab deruxtecan.
  Interventions:

  • Drug: Osimertinib
  • Drug: Datopotamab deruxtecan

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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 2, 2024): 248
• Original Estimated Enrollment (submitted: May 8, 2019): 150
• Estimated Study Completion Date: May 6, 2025
• Estimated Primary Completion Date: May 6, 2025 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark, Italy, Japan, Korea, Republic of, Netherlands, Norway, Spain, Sweden, United States
• Removed Location Countries: Canada

Administrative Information

• NCT Number: NCT03944772
• Other Study ID Numbers: D6186C00001; 2018-003974-29 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

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
• Supporting Materials: 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

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: AstraZeneca
• Verification Date: May 2024