Tepotinib Phase II study in advanced lung cancer harboring MET exon 14 (METex14) skipping alterations and MET amplification

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Healthcare KGaA

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

18 Jul 2016 → 27 Dec 2024

Decision date (initial)

2024-07-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Healthcare KGaA

External identifiers

EU CT number

2024-512003-39-00

EudraCT number

2015-005696-24

ClinicalTrials.gov

NCT02864992

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy, Pharmacogenetic, Pharmacokinetic, Pharmacodynamic

1. PART 1:
COHORT A (METex14 skipping alterations):
- To assess the efficacy of tepotinib in subj. with locally advanced or metast. NSCLC harboring the METex14 skipping alterations or MET amplif., as per objective response acc. to RECIST v. 1.1, based on independent review in
- Subj. positive for METex14 skipping alterations, regardless of MET amplif. status
-Subj. positive for METex14 skipping alterations based on liquid biopsy (LBx), regardless of MET amplification status
-Subj. tested positive for METex14 skipping alterations based on tumor biopsy (TBx), regardless of MET ampl. status.

2. PART 1:
COHORT B (MET amplification):
- To assess the efficacy of tepotinib in subjects with locally advanced or metastatic NSCLC, as per obj. response accord. to RECIST Ver. 1.1, based on independent review in:
- Subj.tested positive for MET amplification in LBx, and negative for METex14 skipping alter.

3. PART 2:
Cohort C (confirm. part for METex14 skipping alterations), ref to protocol

Secondary objectives 7

1. ALL COHORTS To further assess the efficacy of tepotinib
2. To assess tolerability and safety of tepotinib
3. To assess PK of tepotinib and its metabolite(s)
4. To assess Health-Related Quality of Life (HRQoL) Exploratory Objectives
5. To explore the QT/QTc interval concentration relationship based on Cycle 1, Day 1 and Cycle 2, Day 1 data
6. To investigate the exposure-response relationship
7. To explore a possible link between biomarkers of c-Met pathway activation, other relevant oncogenic pathways in plasma, serum and tumor tissue, and the activity of tepotinib

Conditions and MedDRA coding

Lung Cancer

Study design 1 period

Regulatory references

Plan to share IPD

Yes

IPD plan description

We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Histologically or cytologically confirmed advanced (locally advanced or metastatic) NSCLC (all types including squamous and sarcomatoid);
2. 2. Treatment naive patients in first-line or pre-treated patients with no more than 2 lines of prior therapy
3. 3. Subjects with MET alterations, namely METex14 skipping alterations in plasma and/or tissue, as determined by the central laboratory or by an assay with appropriate regulatory status will, be enrolled into the trial. For these subjects, sufficient tumor tissue and/or plasma is requested to allow additional testing MET amplification only in plasma defined by a positive LBx test, as determined by the central laboratory or by an assay with appropriate regulatory status Based on the outcome of the interim analysis in 12 LBx selected subjects: MET amplification only in tissue defined by a positive TBx with a gain of at least 4 copies of the MET gene, as determined by the central laboratory or by an assay with appropriate regulatory status.
4. 4. Signed, written informed consent by subject or legal representative prior to any trial-specific screening procedure;
5. 5. Male or female, ≥ 18 years of age (or having reached the age of majority according to local laws and regulations, if the age of majority is > 18 years of age); [i.e., ≥ 20 years of age in Japan]);
6. 6. Measurable disease in accordance with RECIST version 1.1;
7. 7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
8. 8. A female subjects is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential as defined in Appendix VIII OR b. A woman of childbearing potential who agrees to use a highly effective contraception (i.e., methods with a failure rate of less than 1 % per year) as detailed in in Appendix VII of this protocol 2 weeks before start of first dose of study treatment, during the treatment period and for at least 4 weeks after the last dose of study treatment. Women of childbearing potential must have a negative pregnancy test (β-HCG test in serum) prior to enrollment.
9. 9. A male subject must agree to use and to have their female partners of childbearing potential to use a highly effective contraception (i.e., methods with a failure rate of less than 1 % per year) as detailed in Appendix VII of this protocol from the first dose of study treatment, during the treatment period and for at least 3 months after the last dose of study treatment and refrain from donating sperm during this period. Male subjects should always use a barrier method such as condom concomitantly.

Exclusion criteria 10

1. 1. Subjects with characterized EGFR activating mutations that predict sensitivity to anti-EGFR-therapy, including, but not limited to exon 19 deletions and exon 21 alterations;
2. 2. Subjects with characterized ALK rearrangements; that predict sensitivity to anti-ALK therapy
3. 3. Subjects with symptomatic brain metastases who are neurologically unstable, and/or have required an increase in steroid dose within 2 weeks and/or have received prior stereotactic radiosurgery/gamma knife within 2 weeks and/or other prior treatment for brain metastases within 4 weeks prior to the start of therapy. Subjects with leptomeningeal disease are ineligible;
4. 4. Any unresolved toxicity Grade 2 or more according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) from previous anticancer therapy;
5. 5. Need for transfusion within 14 days prior to the first dose of trial treatment;
6. 6. Prior chemotherapy, biological therapy, radiation therapy, hormonal therapy for anti-cancer purposes, targeted therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of trial treatment
7. 7. Subjects who have brain metastasis as the only measureable lesion
8. 8. Inadequate hematological, liver, renal, cardiac function
9. 9. Prior treatment with other agents targeting the HGF/c-Met pathway;
10. 10. Past or current history of neoplasm other than NSCLC, except for curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least 5 years (for a full list of exlustion criteria please see the study protocol)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective response (confirmed CR or PR) determined according to RECIST Version 1.1, based on independent review.

Secondary endpoints 15

1. 1. Objective response rate assessed as per Investigator
2. 2. Duration of response as assessed by independent review committee
3. 3. Duration of response as assessed by investigator
4. 4. Objective disease control Rate as assessed by independent review committee
5. 5. Objective disease control Rate as assessed by investigator
6. 6. Progression free survival as assessed by independent review committee
7. 7. Progression free survival as assessed by investigator
8. 8. Overall survival
9. 9. Number of subjects with TEAEs and deaths
10. 10. Number of subjects with markedly abnormal vital signs, ECG, physical examination and ECOG PS.
11. 11. Health Related Quality of Life Parameters
12. 12. Maximum plasma concentration (Cmax) of Drug
13. 13. Volume of distribution (Vz/F) of drug
14. 14. Total Clearance (Cl) of drug
15. 15. Number of subjects with markedly abnormal clinical laboratory tests (hematology and coagulation, biochemistry and urinalysis).

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Healthcare KGaA

Sponsor organisation

Merck Healthcare KGaA

Address

Gebaeude D11, 128 F, Frankfurter Strasse 250 128 F Frankfurter Strasse 250

City

Darmstadt

Postcode

64293

Country

Germany

Scientific contact point

Organisation

Merck Healthcare KGaA

Contact name

Global Regulatory Affairs

Public contact point

Organisation

Merck Healthcare KGaA

Contact name

Global Regulatory Affairs

Third parties 3

Locations

7 EU/EEA countries · 21 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