Phase 2 Platform Study in Patients 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:N/A

Recruitment Complete

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.

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

250

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 25 Jun 2019

Estimated Primary Completion Date: 28 Nov 2025

Estimated Study Completion Date: 28 Nov 2025

Study design

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

Verification:

Verified 01 Nov 2023 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

applicable to all study treatment modules (Group A & B)
1. 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 (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.
(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, 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.
(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 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:
a) Absolute neutrophil count < 1.5 × 109/L.
b) Platelet count < 100 × 109/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 + 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: Datopotamab deruxtecan Other Name: DS 1062a

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
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