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

Sponsor

AstraZeneca (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03944772

Collaborator

(none)

210

Enrollment

Locations

Arms

77.1

Anticipated Duration (Months)

3.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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

Anticipated Enrollment :

210 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.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 :

Jun 25, 2019

Anticipated Primary Completion Date :

Nov 28, 2025

Anticipated Study Completion Date :

Nov 28, 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 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

Outcome Measures

Primary Outcome Measures

Objective response rate (ORR) [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

Progression-free survival (PFS) [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) [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) [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 [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 [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 [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

Criteria

Ages Eligible for Study:

18 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria applicable to all study treatment modules (Group A & B)

NSCLC with the following features:
Locally advanced or metastatic disease (ie, advanced NSCLC) not amenable to curative surgery or radiotherapy at study entry.
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
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.

Evidence of radiological disease progression on first-line monotherapy with osimertinib 80 mg po QD.
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.
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.
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.

Exclusion Criteria applicable to all study treatment modules (Groups A/B):

Patients whose disease has progressed within the first 3 months of osimertinib treatment (refractory to osimertinib treatment).
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.

Any unresolved toxicities from prior osimertinib treatment greater than CTCAE Grade 1 at the time of starting study treatment.
Patients should not have discontinued osimertinib >60 days prior to the first dose of study treatment.
Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
Absolute neutrophil count < 1.5 × 109/L.
Platelet count < 100 × 109/L.
Haemoglobin < 9 g/dL.
Alanine transaminase (ALT) > 2.5 × ULN.
Aspartate aminotransferase (AST) > 2.5 × ULN.
Total bilirubin (TBL) > 1.5 × ULN, or > 3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia).
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

	Site	City	State	Country	Postal Code
1	Research Site	Duarte	California	United States	91010
2	Research Site	La Jolla	California	United States	92093
3	Research Site	Los Angeles	California	United States	90048
4	Research Site	Sacramento	California	United States	95817
5	Research Site	Santa Monica	California	United States	90404
6	Research Site	New Haven	Connecticut	United States	06510
7	Research Site	Atlanta	Georgia	United States	30318
8	Research Site	Chicago	Illinois	United States	60612
9	Research Site	Baltimore	Maryland	United States	21224
10	Research Site	Boston	Massachusetts	United States	02114
11	Research Site	Boston	Massachusetts	United States	02215
12	Research Site	Grand Rapids	Michigan	United States	49503
13	Research Site	New York	New York	United States	10017
14	Research Site	New York	New York	United States	10032
15	Research Site	Portland	Oregon	United States	97239
16	Research Site	Pittsburgh	Pennsylvania	United States	15232
17	Research Site	Houston	Texas	United States	77030
18	Research Site	Seattle	Washington	United States	98109
19	Research Site	Edmonton	Alberta	Canada	T6G 1Z2
20	Research Site	Toronto	Ontario	Canada	M5G 2M9
21	Research Site	Herlev		Denmark	2730
22	Research Site	Odense C		Denmark	5000
23	Research Site	Vejle		Denmark	7100
24	Research Site	Catania		Italy	95123
25	Research Site	Napoli		Italy	80131
26	Research Site	Orbassano		Italy	10043
27	Research Site	Padova		Italy	35128
28	Research Site	Varese		Italy	21100
29	Research Site	Chuo-ku		Japan	104-0045
30	Research Site	Fukuoka-shi		Japan	812-8582
31	Research Site	Koto-ku		Japan	135-8550
32	Research Site	Nagoya-shi		Japan	464-8681
33	Research Site	Osaka-shi		Japan	541-8567
34	Research Site	Wakayama-shi		Japan	641-8510
35	Research Site	Seongnam-si		Korea, Republic of	13620
36	Research Site	Seoul		Korea, Republic of	03722
37	Research Site	Seoul		Korea, Republic of	05505
38	Research Site	Seoul		Korea, Republic of	06351
39	Research Site	Amsterdam		Netherlands	1066 CX
40	Research Site	Amsterdam		Netherlands	1081 HV
41	Research Site	Maastricht		Netherlands	6229 HX
42	Research Site	Nijmegen		Netherlands	6525 GA
43	Research Site	Rotterdam		Netherlands	3015GD
44	Research Site	Drammen		Norway	3004
45	Research Site	Oslo		Norway	N-0310
46	Research Site	Trondheim		Norway	7030
47	Research Site	A Coruña		Spain	15006
48	Research Site	Barcelona		Spain	08025
49	Research Site	Barcelona		Spain	08036
50	Research Site	Madrid		Spain	28041
51	Research Site	Madrid		Spain	28046
52	Research Site	Sevilla		Spain	41009
53	Research Site	Stockholm		Sweden	17176
54	Research Site	Uppsala		Sweden	SE-751 85