Advanced or metastatic epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) with acquired resistance to approved EGFR tyrosine kinase inhibitors (TKI)
Conditions
Interventions
Product Name: ALUNBRIG
Product Code: [Brigatinib]
Pharmaceutical Form: Film-coated tablet
CAS Number: 1197953-54-0
Current Sponsor code: Brigatinib
Concentration unit: mg milligram(s)
Concentration ty
Sponsors
FONDAZIONE RICERCA TRASLAZIONALE (FORT)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria Part 1 only 1) Histologically confirmed advanced EGFR mutated or ALK positive or ROS1 positive tumors resistant to available specific inhibitors. Part 2 only 1) Acquired resistance to EGFR TKIs defined as progression of disease according to RECIST 1.1 during osimertinib treatment and presence of on-target mechanism of resistance, i.e. secondary or tertiary resistance mutations of EGFR, on circulating tumor DNA or tumor tissue obtained before treatment start and after any intervening systemic treatment Parts 1 and 2 1) Age 18 years or older 2) Willingness to provide written informed consent. 3) Life expectancy >12 weeks. 4) ECOG performance status of 0 to 1. 5) Presence of measurable disease per RECIST v1.1 as determined by the site study team. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. The lesion selected for pre- and/or post-treatment biopsy cannot be the only measurable lesion. 6) Female patients should be using adequate contraceptive measures, should not be breastfeeding until 120 days 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: a. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments. b. 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. c. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation. Female patients must meet 1 of the following: • Postmenopausal for at least 1 year before the screening visit, or • Surgically sterile, or • If they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing of the informed consent form through 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Brigatinib may decrease effectiveness of hormonal contraceptives, therefore, women are recommended to use non-hormonal methods of contraception. Highly effective non-hormonal birth control for women of child bearing potential with male partners includes: • Sexual abstinence (no sexual intercourse) • Intrauterine device (IUD) or intrauterine system (IUS) • Bilateral tubal ligation (both tubes tied) • Vasectomized partner 7) Male patients should be willing to use barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or completely abstain from heterosexual intercourse Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 32 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 16
Exclusion criteria
Exclusion criteria: 1) Off target mechanisms of actions, such as mutations or amplification of other genes, changes of histology, etc. 2) Lab assessments as follows: a. Absolute neutrophil count 1.5 × institutional ULN). e. Aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase =2.5 × ULN. Subjects with 1) bone metastases and 2) no hepatic parenchymal metastases on screening radiographic examinations may enroll if the alkaline phosphatase is 2.5 × ULN only with medical monitor approval. f. Total bilirubin =1.5 × ULN. g. International normalized ratio or prothrombin time (PT) >1.5 × ULN. h. Activated partial thromboplastin time (aPTT) >1.5 × ULN. 3) Anticancer medications or investigational drugs within the following ranges: a. <14 days for chemotherapy, targeted small-molecule therapy or radiation therapy; b. <28 days or 5-half-lives (whichever is longer) before first dose of investigational combination therapy. 4) Subjects with previous grade 3 or 4 adverse event to anti-EGFR treatment, even if the toxicity is related only to laboratory anomalies and the subjects are asymptomatic 5) History or the presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis 6) Subjects who have not recovered adequately from toxicity and/or complications from surgical intervention prior to starting therapy. 8) Evidence or history of interstitial lung disease or active non-infectious pneumonitis. 9) Concomitant medication with strong inhibitors or inducers of CYP2C8 and CYP3A4. 10) Known active CNS metastases. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks before the first dose of study treatment and no need of changes to corticosteroids dose for the management of neurologic symptoms). 11) Significant, uncontrolled, or active cardiovascular disease, specifically including 12) Major surgery within 30 days of the first dose of brigatinib. Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed. 13) Another primary malignancy other than NSCLC, except for adequately treated nonmelanoma skin cancer or cervical cancer in situ; definitively treated nonmetastatic prostate cancer; or patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy. 14) Symptomatic brain metastasis (parenchymal or leptomeningeal). Patients with asymptomatic brain metastasis or who have stable symptoms that did not require an increased dose of corticosteroids to control symptoms in the past 7 days before the first dose of brigatinib may be enrolled. 15) Current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Patients with leptomeningeal disease and without cord compression are allowed 16) Inability to swallow food or any co
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: There are study two phases with different primary and secondary objectives. Primary objectives: ·Phase 1: To evaluate the safety and tolerability and determine the maximum tolerated dose (MTD) or a pharmacologically active dose (PAD) of brigatinib in combination with cetuximab in patients with advanced EGFR mutation positive cancers and ALK or ROS1 positive tumors who are resistant to available inhibitors. ·Phase 2: To evaluate the activity of brigatinib in combination with cetuximab in EGFR mutation positive NSCLC who develop an on-target mechanism of resistance, i.e. secondary or tertiary resistance mutations of EGFR (secondary/tertiary mutations of EGFR);Secondary Objective: ·Phase 1: To evaluate the activity of brigatinib in combination with cetuximab in patients with EGFR mutated solid tumors and ALK and ROS1 positive tumors that are resistant to available inhibitors. ·Phase 2: To evaluate the safety and tolerability of brigatinib and cetuximab at the MTD or PAD in EGFR mutation positive NSCLC who develop an .on-target mechanism of resistance to available TKIs, i.e. secondary or tertiary resistance mutations of EGFR. ·Phase 2: To evaluate the efficacy of brigatinib in combination with cetuximab in EGFR mutation positive NSCLC who develop a non-target mechanism of resistance to available TKIs, i.e. secondary or tertiary resistance mutations of EGFR.;Primary end point(s): ·Phase 1: Safety and tolerability will be assessed by monitoring the frequency, duration, and severity of adverse events (AEs) through physical examination, changes in vital signs and ECGs, and through clinical laboratory blood and urine sample evaluations. ·Phase 2: Objective response rate, defined as the percentage of subjects having a complete response (CR) or partial response (PR), will be determined by investigator assessment of radiographic disease as per RECIST v1.1.;Timepoint(s) of evaluation of this end point: Phase 1: Continuous - at each medical examination of the pa | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Phase 1: Continuous -every 8 weeks ± 7 days for the first 12 months and then every 12 weeks ± 7 days Phase 2 : Continuous - at each medical examination of the patient Phase 2: Continuous -every 8 weeks ± 7 days for the first 12 months and then every 12 weeks ± 7 days;Secondary end point(s): · Phase 1: Objective response rate, defined as the percentage of subjects having a complete response (CR) or partial response (PR), will be determined by investigator assessment of radiographic disease as per RECIST v1.1 · Phase 2: Safety and tolerability will be assessed by monitoring the frequency, duration, and severity of adverse events (AEs), through physical examinations, changes in vital signs and ECGs, and through clinical laboratory blood and urine sample evaluations · Phase 2: Progression-free survival, defined as the time from date of first dose of study drug until the earliest date of disease progression, as determined by investigator assessment of objective radiographic disease assessments per RECIST v1.1, or death due to any cause, if occurring sooner than progression. | — |
Countries
Italy
Contacts
Public ContactClinical Operations
Clinical Research Technology
Outcome results
None listed