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

Non-Small Cell Lung Cancer Clinical Trial

— 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.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03944772
• Other study ID #: D6186C00001
• Secondary ID: 2018-003974-29
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 25, 2019
• Est. completion date: May 6, 2025

Study information

• Verified date: June 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 248
• Est. completion date: May 6, 2025
• Est. primary completion date: May 6, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer

Intervention

Drug:
• Osimertinib
Osimertinib given orally at 80 mg once daily
• Savolitinib
Savolitinib will be given orally at 300 mg or 600mg once daily
• Gefitinib
Gefitinib given orally at 250 mg once daily
• Necitumumab
Necitumumab given IV at 800 mg on Day 1 and Day 8 of every 3-week cycle
• Durvalumab
Durvalumab given IV at 1500 mg on Day 1 of every cycle
• Carboplatin
Carboplatin given IV on Day 1 of every 21-day cycle for up to 6 cycles
• Pemetrexed
Pemetrexed given IV at 500 mg/m2 body BSA on Day 1 of every cycle
• Alectinib
Alectinib given orally at 600mg twice daily and for Japanese patients at 300mg twice daily.
• Selpercatinib
Selpercatinib given orally at 160mg twice daily
• Selumetinib
Selumetinib given orally at 75 mg twice daily for 4 days, followed by 3 days off treatment
• Etoposide
Etoposide 80-100 mg/m2 given IV on day 1, 2 and 3 of every 21-day cycle for up to 4 cycles.
• Cisplatin
Cisplatin 75-80 mg/m2 given IV on days 1 of each cycle
• Datopotamab deruxtecan
Datopotamab deruxtecan given IV at 4 or 6 mg/kg on Day 1 of every 3-week cycle.

Locations

Country	Name	City	State
Denmark	Research Site	Odense C
Italy	Research Site	Catania
Italy	Research Site	Napoli
Italy	Research Site	Orbassano
Italy	Research Site	Padova
Italy	Research Site	Varese
Japan	Research Site	Chuo-ku
Japan	Research Site	Fukuoka-shi
Japan	Research Site	Koto-ku
Japan	Research Site	Nagoya-shi
Japan	Research Site	Osaka-shi
Japan	Research Site	Wakayama-shi
Korea, Republic of	Research Site	Seongnam-si
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Maastricht
Netherlands	Research Site	Nijmegen
Netherlands	Research Site	Rotterdam
Norway	Research Site	Drammen
Norway	Research Site	Oslo
Norway	Research Site	Trondheim
Spain	Research Site	A Coruña
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Sevilla
Sweden	Research Site	Stockholm
United States	Research Site	Baltimore	Maryland
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boston	Massachusetts
United States	Research Site	Chicago	Illinois
United States	Research Site	Duarte	California
United States	Research Site	Grand Rapids	Michigan
United States	Research Site	Houston	Texas
United States	Research Site	Los Angeles	California
United States	Research Site	New Haven	Connecticut
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Portland	Oregon
United States	Research Site	Sacramento	California
United States	Research Site	Santa Monica	California
United States	Research Site	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Denmark,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Norway,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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).
Secondary	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.
Secondary	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)

External Links

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