T-DM1 and Osimertinib Combination Treatment to Target HER2 Bypass Track Resistance in EGFR Mutation Positive NSCLC

NCT03784599 | Terminated Phase 2

• 1 other identifier: M18TEO
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 5

Brief Summary

This is a single arm open-label multi-center phase II study, investigating disease control rate after 3 months of treatment with trastuzumab-emtansine/osimertinib combination therapy in patients with advanced EGFR mutation positive non-small cell lung cancer (NSCLC) with HER2 bypass track resistance.

Conditions

Carcinoma, Non-Small-Cell Lung

Outcome Measures

Primary Outcomes (2)

• Safety (intensity and incidence of adverse events)

  Safety as indicated by intensity and incidence of adverse events, graded according to NCI CTCAE Version 4.03

  Up to 30 days after last study drug intake

• Objective response rate according to RECIST v1.1 after 3 months of treatment

  Complete response and partial response after 3 months of treatment

  From date of registration until 3 months.

Secondary Outcomes (3)

• Progression-free survival

  From date of registration until the date of first documented progression up to 100 months

• Disease control rate, after 3 months of treatment

  From date of registration until 3 months.

• Overall survival

  From date of registration until the date of death from any cause, assessed up to 100 months.

Other Outcomes (1)

• Genetic profiling to assess predictors of response and resistance - circulating free (cf)DNA

  At baseline, every 6 weeks and at treatment discontinuation (expected 6 months after start)

Study Arms (1)

Trastuzumab-emtansine and osimertinib

EXPERIMENTAL

Trastuzumab-emtansine 3.6 mg/kg, intravenously, every 3 weeks Osimertinib 80 mg once daily, orally, continuous Treatment will be continued until tumor progression (according to RECIST v1.1) confirmed by tumor imaging, unacceptable toxicity, or death occurs.

Drug: Trastuzumab emtansine; Drug: Osimertinib

Interventions

Trastuzumab emtansine DRUG

Infusion

Trastuzumab-emtansine and osimertinib

Osimertinib DRUG

Tablet

Trastuzumab-emtansine and osimertinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically confirmed stage IV non-squamous NSCLC, characterized by an activating EGFR mutation.
• Progressive disease according to RECIST 1.1 on first (gefitinib, erlotinib), second (afatinib) or third (osimertinib) 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:
• 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.
• 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.
• Patients need At least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
• 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 the 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 screening.
• 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

You may not qualify if:

• Uncontrolled infectious disease.
• Other active malignancy. Patients with a history of cancer for which treatment is complete and with no evidence of malignant disease currently cannot be enrolled if their chemotherapy was completed less than 6 months prior and/or have received a bone marrow transplant less than 2 years before the first day of study treatment.
• 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:
• Patients with pre-treatment LVEF \< 55%.
• Prior history of congestive cardiac failure; LVEF decline to \<50% on previous treatment with HER2 agents
• Conditions impairing LV function e.g. uncontrolled hypertension
• MI/unstable angina within 6 months or serious cardiac arrhythmia
• Any of the following cardiac criteria:
• Mean resting corrected QT interval (QTc) \> 470 msec obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value
• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block.
• 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.
• Inadequate bone marrow reserve or organ function, as demonstrated by any of the following laboratory values:

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• AstraZeneca: collaborator
• Roche Pharma AG: collaborator

Study Sites (5)

Maastricht UMC+

Maastricht, Limburg, 6229 HX, Netherlands

Location

VU medical center

Amsterdam, North Holland, 1007 MD, Netherlands

Location

Antoni van Leeuwenhoek ziekenhuis - Netherlands Cancer Institute

Amsterdam, North Holland, 1066 CX, Netherlands

Location

Erasmus MC

Rotterdam, South Holland, 3015 GD, Netherlands

Location

Univercity Medical Center Groningen

Groningen, 9713 GZ, Netherlands

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Ado-Trastuzumab Emtansine; osimertinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Maytansine; Macrolides; Lactones; Organic Chemicals; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Trastuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• J. de Langen, MD, PhD

  NKI-AvL

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2018
• First Posted: December 24, 2018
• Study Start: December 18, 2018
• Primary Completion: May 17, 2021
• Study Completion: May 17, 2021
• Last Updated: November 10, 2022

Record last verified: 2022-11

Locations

NL (5)