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Carcinoma, Non-Small-Cell LungPhase 2TRAEMOSNCT03784599

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

A Phase 2 study testing Trastuzumab emtansine and Osimertinib in people with Carcinoma, Non-Small-Cell Lung, run by The Netherlands Cancer Institute at 5 sites in Netherlands.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Carcinoma, Non-Small-Cell Lung
What is being tested?
Trastuzumab emtansine and Osimertinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
28 participants
Where
5 sitesNetherlands
Study dates
18 Dec 2018to 17 May 2021
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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

Who cannot join

  • 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:
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  • 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:
  • Hematology: hemoglobin <5.6 mmol/L, absolute neutrophil count <1.5 x 10^9/L, platelet count <100 x 10^9/L.
  • Biochemistry: alanine aminotransferase, aspartate aminotransferase and bilirubin ≤ 2.5 x ULN, except in the case of liver metastases where these values must be ≤ 5x ULN.
  • Kidney function: serum creatinine >1.5 x ULN concurrent with creatinine clearance <50 ml/min (measured or calculated by Cockroft and Gault equation).
  • Patients with symptomatic central nervous system metastases who are neurologically unstable. Unstable brain metastases except for those who have completed definitive therapy and have had a stable neurological status for 2 weeks after completion of definitive therapy. Patients may be on corticosteroids to control brain metastases if they have been on a stable dose for 2 weeks prior to the start of study treatment and are clinically asymptomatic.
  • Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow osimertinib or previous significant bowel resection that would preclude adequate resorption of osimertinib.
  • 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.
  • Treatment with an investigational drug within five half-lives of the compound or 3 months, whichever is greater
  • Currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 week prior) (Appendix C). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.
  • Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment, with the exception of alopecia and grade 2, prior platinum-therapy-related neuropathy.
  • Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
  • Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease.

Trial locations and contacts

5 sites in 1 country.

5 sites in 1 country

Netherlands5 sites

  • VU medical center

    Amsterdam, North Holland, 1007 MD

  • Antoni van Leeuwenhoek ziekenhuis - Netherlands Cancer Institute

    Amsterdam, North Holland, 1066 CX

  • Univercity Medical Center Groningen

    Groningen, 9713 GZ

  • Maastricht UMC+

    Maastricht, Limburg, 6229 HX

  • Erasmus MC

    Rotterdam, South Holland, 3015 GD

Other trials in Netherlands

About this study

Official title: Trastuzumab-emtansine and Osimertinib Combination Treatment to Target HER2 Bypass Track Resistance in EGFR Mutation Positive NSCLC

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.

Read the detailed description

This study is a multicenter single arm phase II study with a phase I run in to study the toxicity and efficacy of T-DM1 and osimertinib combination treatment in patients with EGFR mutated NSCLC and HER2 bypass track activation (HER2 immunohistochemistry (IHC) ≥2+ and/or HER2 amplification) after progression on an EGFR TKI.

In the phase I run in, study safety will be assessed in a classical 3+3 design. Because of potential for overlapping hematologic and non-hematologic adverse events (AE), the first 3 patients will receive a reduced dose of T-DM1 3.0 mg/kg IV every 3 weeks combined with osimertinib 80 mg once daily. Dose-limiting toxicity (DLT) is defined as a grade 3 AE toxicity according to CTC AE 4.03 that does not recover to grade ≤2 before the next cycle of T-DM1. DLT's will be collected up to 6 weeks after treatment initiation (2 T-DM1 cycles). Dose escalation within patients is not allowed.

If 1 patient develops a dose-limiting toxicity (DLT), 3 more will be included and treated with T-DM1 3.0 mg/kg. If ≥2 of the 6 patients develop a DLT, further study of the combination will be halted. Otherwise, T-DM1 3.0 mg/kg IV every 3 weeks combined with osimertinib 80 mg once daily will be the maximum tolerated dose (MTD) to put forward in the phase II part of this study.

If none of the first three patients develops a DLT, the T-DM1 dose will be escalated to the standard dose of 3.6 mg/kg. If ≤1 patient experiences a DLT in 6 patients (3+3), T-DM1 3.6 mg/kg IV every 3 weeks and osimertinib 80 mg once daily will be the MTD. If ≥2 patients develop a DLT, the T-DM1 will be lowered to 3.0 mg/kg and three more patients will be enrolled in this dose cohort. When ≤1 of these patients develops a DLT, this will be the MTD.

Being tested
Trastuzumab emtansine, Osimertinib
Medical subject headings
Carcinoma, Non-Small-Cell Lung

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT03784599
Study groupRoleWhat they receive
Trastuzumab-emtansine and osimertinibExperimentalTrastuzumab-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.
Receives: Drug: Trastuzumab emtansine; Drug: Osimertinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: Up to 30 days after last study drug intake

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

    Complete response and partial response after 3 months of treatment

    Measured: From date of registration until 3 months.

Secondary outcomes (3)

  1. 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, whichever comes first

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

  2. Disease control rate, after 3 months of treatment

    DCR, defined as the percentage of patients with stable disease (SD), partial response (PR) or complete response (CR)

    Measured: From date of registration until 3 months.

  3. Overall survival

    OS, defined as the time from first administration of the study drug combination to lost to follow up or death, whichever comes first

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Dec 2018
  2. Study start18 Dec 2018
  3. Primary completion17 May 2021
  4. Study completion17 May 2021

Why it stopped: insufficient effectiveness

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
28 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03784599
Sponsor's protocol ID
M18TEO
Acronym
TRAEMOS
Status last verified
Nov 2022
First submitted
31 Oct 2018
Last updated
10 Nov 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Trastuzumab emtansine and Osimertinib in people with Carcinoma, Non-Small-Cell Lung, run by The Netherlands Cancer Institute at 5 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 10 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: insufficient effectiveness). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Safety (intensity and incidence of adverse events) (time frame: Up to 30 days after last study drug intake). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03784599.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Nov 2022.

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