Combination treatment with trastuzumab-emtansine and osimertinib to treat patients with advanced EGFR mutated non small cell lung cancer with HER2 tumor expression after progressive disease during EGFR targeted therapy
- Conditions
- Advanced EGFR mutation positive non small cell lung cancer with HER2 bypass track resistanceMedDRA version: 20.0 Level: PT Classification code 10029522 Term: Non-small cell lung cancer stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2018-002885-38-NL
- Lead Sponsor
- Stichting Het Nederlands Kanker Instituut-Antoni van Leuewenhoek Ziekenhuis
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- Not specified
- Target Recruitment
- 58
-Histologically or cytologically confirmed stage IV non-squamous NSCLC, characterized by an activating EGFR mutation.
-Progressive disease according to RECIST 1.1 on first, second or third generation EGFR TKI and still receiving the drug.
-A rebiopsy after having acquired resistance to a first, second or third generation TKI-treatment must have been performed and be:
a. Negative for T790M in case of treatment with a first or second generation EGFR TKI. After progression on a third generation EGFR TKI patients may either be positive or negative for T790M.
b. Positive for HER2-overexpression (positive membranous immunohistochemistry staining IHC =2+ (on a scale of 0-3) in =10% of the cells) must have been detected.
-There must be at least one measurable disease site, according to RECIST 1.1 criteria.
-Absence of symptomatic brain metastases. All patients will be scanned at baseline with a brain MRI.
-Patients must be willing and able to comply with the protocol for the duration of study including undergoing treatment and scheduled visits and examinations.
-World Health Organization (WHO) performance status 0-2.
-Patients must have a life expectancy =12 weeks.
-Ability to give written informed consent before patient registration.
-Patients must be =18 years of age.
-Men and women of child bearing potential should be willing to take adequate contraceptive measures during the study and until three months after study drug discontinuation.
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 30
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 28
-Uncontrolled infectious disease.
-Other active malignancy.
-Major surgery (excluding diagnostic procedures like e.g. mediastinoscopy or VATS biopsy) in the previous 4 weeks.
-Known hypersensitivity to T-DM1 or osimertinib (or drugs with a similar chemical structure or class) or any excipients of these agents.
-Previous treatment with a HER2 monoclonal antibody.
-Clinically significant cardiac disease or a Left Ventricular Ejection Fraction (LVEF) of <40%.
-Inadequate bone marrow reserve or organ function, as demonstrated by any of the following laboratory values: Haematology: haemoglobin <5.6mmol/L, absolute neutrophil count <1.5 x 10^9/L, platelet count <100 x 10^9/L. Biochemistry: alanine aminotransferase, aspartate aminotransferase and bilirubin = 3x ULN, except in the case of liver metastases where these values must be = 5x ULN. Creatinine clearance <50 ml/min (measured or calculated by Cockroft and Gault equation).
-Patients with symptomatic central nervous system metastases who are neurologically unstable.
-Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow osimertinib or previous significant bowel resection that would preclude adequate resorption of osimertinib.
-Patients on anticoagulant treatment will not be excluded, but should be monitored closely during T-DM1 treatment.
-Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (serum) pregnancy test prior to study entry.
-Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <br> Main Objective: -To evaluate the safety of the combination treatment of T-DM1 and osimertinib. Safety will be collected for 6 weeks (2 cycles each of 3 weeks) after initiation of each dose. <br> -To determine the MTD/recommended phase II dose (RP2D).<br> -To assess the objective response rate (ORR) of T-DM1 and osimertinib combination treatment.<br> ;<br> Secondary Objective: -To evaluate the safety of the combination treatment of T-DM1 and osimertinib. <br> -To assess progression-free survival (PFS).<br> -To assess disease control rate (DCR) after 3 months of treatment.<br> -To assess overall survival (OS).<br> ;<br> Primary end point(s): (S)AEs according to CTC AE 4.03. <br> Objective response rate according to RECIST v1.1 after 3 months of treatment.<br> ;Timepoint(s) of evaluation of this end point: 3 months
- Secondary Outcome Measures
Name Time Method <br> Secondary end point(s): (Serious) Adverse Events, (S)AEs according to CTC AE 4.03. <br> Progression free survival (PFS), defined as the time from first administration of the study drug combination to disease progression by RECIST v1.1. or lost to follow up or death.<br> Disease control rate (DCR), defined as the percentage of patients with stable disease (SD), partial response (PR) or complete response (CR).<br> Overall survival (OS), defined as the time from first administration of the study drug combination to lost to follow up or death.<br> ;<br> Timepoint(s) of evaluation of this end point: Response rates and survival: 6 weekly until progression or death<br> Safety: 3 weekly during treatment, thereafter every 6 weeks<br>