A randomized, non-comparative, phase II study investigating the best epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) sequence in advanced or metastatic non-small-cell lung cancer (NSCLC) harboring EGFR mutations

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Ricerca Traslazionale

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Mar 2020 → ongoing

Decision date (initial)

2025-01-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518223-29-00

EudraCT number

2019-002869-35

ClinicalTrials.gov

NCT04811001

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the best drug sequencing in patients with advanced or metastatic EGFR
mutation positive NSCLC. The study, including patients with classical or uncommon
activating EGFR mutations, will allow to investigate the efficacy of dacomitinib or
osimertinib in these patients. Patients with asymptomatic or controlled brain
metastases are eligible, allowing to define efficacy of dacomitinib in this special
population.

Secondary objectives 1

1. OS in patients treated with osimertinib first followed by dacomitinib and in patients treated with dacomitinib first followed by osimertinib • PFS at the time of study second-line therapy failure (PFS2) in patients treated with front-line osimertinib or dacomitinib; • PFS in patients treated with osimertinib first or dacomitinib first; • Response Rate (RR) with dacomitinib or osimertinib; • RR, PFS and OS with osimertinib followed by dacomitinib or with the opposite sequence in patients with uncommon activating EGFR mutations; • RR, PFS and OS with dacomitinib given at the time of osimertinib failure; • Intracranial RR and intracranial PFS with dacomitinib or osimertinib • Safety and incidence of AEs in patients treated with osimertinib followed by dacomitinib or with the opposite sequence.

Conditions and MedDRA coding

Advanced or metastatic untreated EGFR mutation positive NSCLC

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 1) Written informed consent; 2) Male or female patient aged =18 years; 3) Histologically/cytologically confirmed diagnosis of stage IIIB/IV NSCLC with evidence of activating EGFR mutations including exon 19 deletion, exon 21 L858R or other activating/sensitizing EGFR mutations such as exon 21 L861Q, exon 18 G719S, G719A, G719C, exon 20 S768I and V769L; co-occurrence of de novo T790M is not an exclusion criterion; EGFR status assessed in circulating DNA is allowed; 4) Patients eligible and candidate to receive osimertinib as first- or second-line treatment according to clinical practice and study design, as decided by Investigator regardless study participation; 5) Patients with brain metastases are allowed provided they are asymptomatic and stable (i.e. without evidence of progression by imaging for at least two weeks prior to the first dose of trial treatment and without deterioration of any neurologic symptoms); 6) No evidence of concomitant drivers including KRAS mutations, HER2 mutations, ALK or ROS1 rearrangements, MET mutations, BRAF mutations; 7) No previous EGFR-TKI therapy; Previous palliative radiotherapy or surgery allowed. Prior brain radiotherapy and Stereotactic Radiosurgery (SRS) are allowed. Previous neo/adjuvant chemotherapy is allowed as long as therapy was completed at least 6 months before diagnosis of advanced or metastatic NSCLC; 8) At least one radiological measurable disease according to RECIST criteria version 1.1; 9) Performance status 0-1 (ECOG PS); 10) Patient compliance to trial procedures; 11) Adequate bone marrow function (ANC = 1.5x109/L, platelets =100x109/L, haemoglobin >9 g/dl); 12) Adequate liver function (AST (SGOT)/ALT (SGPT) =2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =5x ULN, bilirubin < grade 2, transaminases no more than 3xULN/<5xULN in presence of liver metastases); 13) Normal level of alkaline phosphatase, and creatinine; 14) Female patients should be using adequate contraceptive measures and should not be breastfeeding, until 4 months after the last dose, and must have a negative pregnancy test (serum or urine) prior to first dose of study drug (within 72 hours); or female patients must have an evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: • Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments. • Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution. • Documentation of irreversible surgical by hysterectomy, bilateraloophorectomy, or bilateral salpingectomy but not tubal ligation. 15) Male patients should be willing to use barrier contraception, i.e. condoms; 16) No significant comorbidity that according to the investigator would hamper the participation on the trial;

Exclusion criteria 1

1. 1) Previous therapy with any EGFR-TKI; 2) Previous systemic anti-cancer therapy for advanced/metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug; 3) Absence of measurable lesions; 4) Concomitant radiotherapy or chemotherapy; 5) Symptomatic or immediately requiring therapy brain metastases or carcinomatous meningitis. Subjects with asymptomatic and stable or treated brain metastases may participate; 6) Diagnosis of any other malignancy during the last 3 years, except for in situ carcinoma of cervix uteri and squamous cell carcinoma of the skin; 7) History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis (but not history of prior radiation pneumonitis); 8) Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, or active infection; 9) Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of the study drugs; 10) Any of the following cardiac criteria: • Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs using local clinic ECG machine-derived QTcF value; • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, e.g., complete left bundle branch block, third-degree heart block, seconddegree heart block, PR interval >250 msec or history of episodes of bradycardia (<50 BPM); • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval; • Abnormal cardiac function: LVEF < 50% (assessed by MUGA or ECHO) 11) Pregnancy or lactating female; 12) Other serious illness or medical condition potentially interfering with the study. E.4.EN - Principal exclusion criteria (up to 4000 characters) (Criteri di esclusione principali, in inglese)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. OS in patients treated with osimertinib first or dacomitinib first

Secondary endpoints 1

1. • OS in patients treated with osimertinib first followed by dacomitinib and in patients treated with dacomitinib first followed by osimertinib • PFS at the time of study second-line therapy failure (PFS2) in patients treated with front-line osimertinib or dacomitinib; • PFS in patients treated with osimertinib first or dacomitinib first; • Response Rate (RR) with dacomitinib or osimertinib; • RR, PFS and OS with osimertinib followed by dacomitinib or with the opposite sequence in patients with u

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Ricerca Traslazionale

Sponsor organisation

Fondazione Ricerca Traslazionale

Address

Via Dei Santi Quattro 61

City

Rome

Postcode

00184

Country

Italy

Scientific contact point

Organisation

Fondazione Ricerca Traslazionale

Contact name

Federico Cappuzzo

Public contact point

Organisation

Fondazione Ricerca Traslazionale

Contact name

Federico Cappuzzo

Locations

2 EU/EEA countries · 38 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications