Clinical trial NCT03944772: 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.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Keywords: 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
BRAF V600E
ALK rearrangement
RET rearrangement
ROS1 rearrangement
NTRK fusion
KRAS G12C
Datopotamab deruxtecan
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2019-05-10
Enrollment: 247
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Objective response rate (ORR)
timeFrame: Measured from first dose until confirmed response or progression. For each patient this is expected to be 3 months on average
Secondary outcomes:
measure: Progression-free survival (PFS)
timeFrame: Measured from first dose until progression. For each patient this is expected to be 6 months on average
measure: Duration of response (DoR)
timeFrame: Measured from response until progression. For each patient this is expected to be 6 months on average
measure: Overall survival (OS)
timeFrame: Measured from first dose until death or final cohort data cut-off. For each patient this is expected to be 20 months on average
measure: Plasma/serum concentrations of therapeutic agents
timeFrame: 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).
measure: Plasma/serum concentrations of therapeutic agents
timeFrame: 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.
measure: 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
timeFrame: Continuously from first dose to end of safety follow up after study treatment discontinuation (approximately up to 21 Months)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Sacramento
country: United States
facility: Research Site
state: California
city: Santa Monica
country: United States
facility: Research Site
state: California
city: New Haven
country: United States
facility: Research Site
state: Connecticut
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Grand Rapids
country: United States
facility: Research Site
state: Michigan
city: New York
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Houston
country: United States
facility: Research Site
state: Texas
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Odense C
country: Denmark
facility: Research Site
city: Catania
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Orbassano
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Varese
country: Italy
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Fukuoka-shi
country: Japan
facility: Research Site
city: Koto-ku
country: Japan
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
city: Osaka-shi
country: Japan
facility: Research Site
city: Wakayama-shi
country: Japan
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Maastricht
country: Netherlands
facility: Research Site
city: Nijmegen
country: Netherlands
facility: Research Site
city: Rotterdam
country: Netherlands
facility: Research Site
city: Drammen
country: Norway
facility: Research Site
city: Oslo
country: Norway
facility: Research Site
city: Trondheim
country: Norway
facility: Research Site
city: A Coruña
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
name: Helena A Yu, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.