The main objective of this study is to assess the efficacy of tepotinib combined with osimertinib inparticipants with advanced or metastatic EGFRm+ NSCLC and MET amplification, determined centrally by FISH.The secondary objectives are the following:…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is objective response (confirmed complete response [CR] or
partial response [PR]) determined according to Response Evaluation Criteria in
Solid Tumors (RECIST) Version 1.1 as per Independent Review Committee (IRC).
Secondary outcome
The secondary endpoints are:
- Objective response (complete response [CR] or partial response [PR])
determined according to Response Evaluation Criteria in Solid Tumors (RECIST)
Version 1.1 as per Independent Review Committee (IRC).
- Occurrence of Adverse Events (AEs) and treatment related AEs.
- Occurrence of abnormalities (Grade >= 3) in laboratory test values (hematology
and coagulation, biochemistry) and urinalysis.
- Occurrence of markedly abnormal vital sign measurements, change in body
weight, and Eastern Cooperative Oncology Group (ECOG) performance status.
- Occurrence of clinically significantly abnormal electrocardiograms (ECGs).
- Objective response according to RECIST Version 1.1 assessed by Investigator.
- Confirmed CR assessed by IRC and by Investigator.
- Duration of response assessed from CR or PR until progressive disease (PD),
death, or last tumor assessment assessed by IRC and by Investigator.
- Disease control (confirmed CR + PR or stable disease [SD] lasting at least 12
weeks) as assessed by IRC and by Investigator.
- Progression free survival according to RECIST Version 1.1 by IRC and by
Investigator.
- Overall survival
- Patient-reported outcomes/health-related quality of life as reported using
the following:
• EuroQol Five Dimension Five Level Scale
• European Organisation for Research and Treatment of Cancer Quality of Life
Questionnaire C30
• Non-Small Cell Lung Cancer Symptom Assessment Questionnaire.
- Single- and multiple-dose PK profile of osimertinib, tepotinib, and their
metabolites including but not limited to AUC0-t, Cmax, and tmax after first
dose (Day 1) and after multiple study intervention dose administrations (Day
15) (safety run-in).
- Population PK profile of osimertinib, tepotinib, and their metabolites,
including, but not limited to, CL/f and VZ/f based on sparse PK sampling on Day
1, Cycle 1 and 2.
- Mutation status in EGFR and other pathways.
Background summary
Lung cancer remains the leading cause of cancer death worldwide. Approximately
85% of patients have (non-small cell lung cancer) NSCLC and most present with
advanced stage disease (not amenable to curative intent). Novel targeted
therapies that interfere with specific molecular signaling pathways have
emerged as a new standard option for selected patients with epidermal growth
factor receptor (EGFR) mutation, including the oral EGFR-TKIs. EGFR-TKIs
inhibit the intracellular tyrosine kinase domain of the EGFR and therefore
block the signal transduction pathways implicated in the proliferation and
survival of cancer cells.
Unfortunately, most patients ultimately progress on epidermal growth factor
receptor tyrosine kinase inhibitors (EGFR TKI) treatment via a resistance
mechanism most commonly related to EGFR such as the T790M mutation (Sullivan et
al. 2017). This limitation has been overcome by the introduction of 3rd
generation TKIs, particularly osimertinib. Currently, osimertinib is the only
3rd generation EGFR TKI approved for the treatment of T790M positive patients
who have progressed on 1st or 2nd generation EGFR TKIs. Osimertinib is also
approved as first-line therapy for advanced EGFR mutant (EGFRm+) NSCLC,
regardless of T790M mutation status. However, despite the robust clinical
activity exerted by osimertinib, patients inevitably develop secondary
resistance to this treatment, which poses a significant challenge due to the
paucity of post-osimertinib pharmacological options available to date (Leonetti
et al. 2019).
Next to EGFR-related resistance, MET gene amplification constitutes the most
frequent cause of bypass pathway activation as an acquired resistance mechanism
to EGFR TKIs (Wu et al. 2017). When osimertinib was given as a first-line
therapy, MET amplification was the most common resistance mechanism,
encountered in 15% of patients. Tepotinib is a novel, highly selective,
reversible adenosine triphosphate (ATP)-competitive, small molecule inhibitor
of MET. Tepotinib has already shown signals of clinical efficacy in the
previous INSIGHT study (NCT01982955) in patients with MET amplified, EGFR
TKI-relapsed, T790M-negative, NSCLC in combination with the 1st generation EGFR
TKI gefitinib (Wu et al. 2018).
Based on the available preclinical and clinical experience with tepotinib in
combination with EGFR-TKIs, the INSIGHT 2 study (MS200095-0031) will
investigate the combination of osimertinib and tepotinib in patients who
relapsed on previous first-line osimertinib due to MET amplification. The study
introduces a single agent tepotinib arm to additionally assess the contribution
of tepotinib to the osimertinib and tepotinib combination therapy. There is
currently no personalized treatment option available for these selected NSCLC
patients and therefore constitutes a clinical condition with high unmet medical
need.
Study objective
The main objective of this study is to assess the efficacy of tepotinib
combined with osimertinib in
participants with advanced or metastatic EGFRm+ NSCLC and MET amplification,
determined centrally by FISH.
The secondary objectives are the following:
To assess the efficacy of tepotinib combined with osimertinib in participants
with advanced or metastatic EGFRm+ NSCLC and MET amplification determined
centrally by blood-based next generation
sequencing.
To assess the efficacy of tepotinib monotherapy in participants with advanced
or metastatic EGFRm+ NSCLC and MET amplification determined centrally by FISH.
To assess tolerability and safety in participants with advanced or metastatic
EGFRm+ NSCLC and MET amplification treated with the combination of tepotinib
plus osimertinib.
To assess tolerability and safety in participants with advanced or metastatic
EGFRm+ NSCLC and MET amplification treated with tepotinib monotherapy.
To further assess efficacy of tepotinib combined with osimertinib in
participants with advanced or metastatic EGFRm+ NSCLC and MET amplification,
determined centrally by FISH
Study design
A Phase II two-arm, open-label study.
Intervention
Study participation is composed of the following stages:
1. Prescreening (performed after progression on first-line osimertinib): After
providing written Prescreening consent, MET amplification status will be
assessed centrally by FISH or by reviewing pre-existing local FISH results
using tumor tissue (TBx), and centrally by blood-based next generation
sequencing (LBx).
2. Screening: After providing written consent at Screening, study eligibility
will be assessed within -28 to -1 days prior to Day 1 of study intervention.
3. Treatment period:
a. For the safety run-in, an initial subset of at least 6 participants, who are
detected to be MET amplified with any of the methods (central/local TBx or
central LBx) described at Prescreening, will be enrolled to confirm the
combination dose of tepotinib 500 mg once daily and osimertinib 80 mg once
daily; the decision will be made by the Safety Monitoring Committee (SMC) based
on predefined dose-limiting toxicity criteria and supported by a Bayesian
Optimal Interval Design (BOIN).
b. For the main treatment, eligible participants who are detected to be MET
amplification positive by central or local FISH (TBx) will be randomly assigned
in a ratio of 2:1 to either the combination of tepotinib at a dose defined by
the SMC and osimertinib at the recommended daily dose of 80 mg or tepotinib
alone at the daily dose of 500 mg (as currently used in the Phase II single
agent VISION study) in cycles of 21-day duration until disease progression
(according to RECIST Version 1.1), death, adverse event (AE) leading to
discontinuation, study withdrawal or consent withdrawal.
4. Treatment follow-ups (for all participants): End of Treatment (EoT) Visit
will be conducted within 14 days after last dose of study intervention.
5. Safety follow-up Visit (for all participants): 30 ± 3 days after the last
dose of study intervention for those who discontinue study intervention
permanently.
Participants who discontinue study intervention for reasons other than
(progressive disease) PD or death will have additional visits for tumor
assessments every 6 weeks until 9 months after first administration of study
intervention and every 12 weeks thereafter until disease progression. Survival
follow-up is to be performed every 3 months (± 2 weeks) at clinic visits or by
telephone contact.
Study burden and risks
In a pharmaceutical trial like this one, every risk or side effect cannot be
predicted. Each person*s reaction to a test drug may be different. Based on
data available from participants having received 500 mg tepotinib monotherapy
once daily, the most frequently observed adverse events (in >=15% of
participants) irrespective of severity and relationship to tepotinib were:
blood creatinine increased; constipation (blockage of stool); decreased
appetite'; diarrhea (loose stool); edema peripheral (swelling caused by excess
fluid); fatigue (feeling tired); hypoalbuminemia (low level of albumin in the
blood, which can cause swelling, muscle weakness, and cramps); nausea (feeling
sick); dyspnea (labored breathing). Liver failure that rarely leads to death
may occur in participants with hepatocellular cancer and extensive liver
involvement from metastases in other disease settings (including NSCLC).
Very common side effects of osimertinib (observed in 10% or more of people
taking osimertinib) include diarrhea (loose stool); nausea; rash; dry skin;
pruritus (itching skin); problems with the eyes; nail toxicity (changes in the
nails, including redness, tenderness, pain, inflammation, brittleness,
separation from nailbed, and shedding); stomatitis (mouth ulcers);
constipation; fatigue (feeling tired); decreased appetite; cough; back pain;
headache; lack of healthy red blood cells that carry oxygen (anemia); decreased
numbers of several types of white blood cells; decreased numbers of platelets
in your blood; high levels of magnesium in the blood; low blood levels of
sodium in the blood.
Osimertinib may cause uncommon but serious side effects, including lung
problems, heart problems, and eye problems. In clinical research studies, 3.9%
of participants experienced interstitial lung disease (ILD), a disorder which
may cause scarring of the lung, and 2.6% of participants experienced
cardiomyopathy, a type of heart disease. These lung and heart problems may, in
the worst case, lead to death. In addition, some participants experienced
keratitis, an inflammation of the surface of the eye, which may cause impaired
eyesight, redness, pain, and light sensitivity. Osimertinib is also known to
cause harm to an unborn baby.
Frankfurter Str. 250
Darmstadt 64293
DE
Frankfurter Str. 250
Darmstadt 64293
DE
Listed location countries
Age
Inclusion criteria
Participants are eligible to be included in the study only if all the following
criteria apply:
1. Are >= 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 [ie, >=
20 years of age in Japan]), at the time of signing the informed consent.
2. Are participants with the following:
a) Locally advanced or metastatic NSCLC histology (confirmed by either
histology or cytology) with documented activating EGFR mutation
b) Presence of at least 1 independently verified measurable lesion in
accordance with RECIST 1.1, that can be accurately assessed at baseline with >=
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), which
is suitable for accurate repeated measurements and that preferably was not
previously irradiated or biopsied
c) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a
minimum life expectancy of 12 weeks
d) Acquired resistance on previous first-line-osimertinib. Participants must
meet both of the following 2 criteria:
-Radiological documentation of disease progression first-lineosimertinib.
-Objective clinical benefit documented during previous osimertinib therapy,
defined by either partial or complete radiological response, or durable stable
disease (SD) (SD should last > 6 months) after initiation
of osimertinib
e) Have received only first line osimertinib as a prior line of therapy in the
noncurative advanced or metastatic NSCLC setting
f) MET amplification as determined by either FISH testing (central or local) on
tumor tissue (TBx) or central blood-based next generation sequencing (LBx).
Tumor and blood samples must be collected following progression on prior
first-line osimertinib at Prescreening.
-Submission of tumor tissue and blood sample obtained after progression on
first line osimertinib, is mandatory for all patients for MET amplification
testing.
-Submission of tumor tissue during Prescreening or Screening is mandatory for
patients with tumor tissue tested by local FISH, to confirm MET amplification
status. Central testing is not mandated prior to the start of study treatment
3. Woman: no woman of childbearing potential (WOCBP) or, use a highly effective
contraception. Man: contraception or no intercourse with a WOBCP.
Exclusion criteria
Participants are excluded from the study if any of the following criteria apply:
1. Spinal cord compression or brain metastasis unless asymptomatic, stable or
not requiring steroids for at least 2 weeks prior to start of study
intervention. Prior radiotherapy or surgery for brain metastases such as
stereotactic radiosurgery/gamma knife must have been completed >= 2 weeks, all
others >= 4 weeks prior to start of therapy. Participants with leptomeningeal
disease are ineligible.
2. Any unresolved toxicity Grade 2 or more according to National Cancer
Institute-Common Terminology Criteria for Adverse Events Version (NCI-CTCAE)
version 5, from previous anticancer therapy with the exception of alopecia.
3. Need for transfusion within 14 days prior to the first dose of study
intervention.
4. Participants who have brain metastasis as the only measurable lesion
5. Inadequate hematological function:
- Hemoglobin < 8.5 g/dL
- Neutrophils < 1.5 × 109/L
- Platelets < 100 × 109/L.
6. Inadequate liver function:
- Total bilirubin > 1.5 × ULN
- AST/ALT/ALP > 3 × ULN
- For participants with liver metastases:
i. Total bilirubin > 1.5 × ULN
ii. AST/ALT/ALP > 5 × ULN
iii. For participants with bone metastases: ALP > 5 × ULN.
7. Inadequate renal function:
- Renal impairment as evidenced by serum creatinine >= 1.5 × ULN, or creatinine
clearance (CrCl) < 30 mL/min calculated by the Cockcroft- Gault formula
(24-hour CrCl might be requested by the Investigator for confirmation, if
calculated CrCl is < 50 mL/min. In such case, participants with 24-hour CrCl <
30 mL/min should be excluded). CrCl (mL/min) = [(140 - age(year)) × weight(kg)]
72 × serum creatinine (mg/dL) {× 0.85 for females}
8. History of ILD or interstitial pneumonitis including radiation pneumonitis
that required steroid treatment.
9. Impaired cardiac function:
-Left ventricular ejection fraction < 45% defined by echocardiography
- Grade 4 arrhythmia (NCI-CTCAE v5.0)
-Serious arrhythmia
-Unstable angina pectoris
-Congestive Heart Failure New York Heart Association III and IV
- Myocardial infarction, stroke, or transient ischemic attack within the last 6
months prior to study entry.
10. Corrected QT interval by Fredericia (QTcF) > 470 ms for women and
> 450 ms for men at screening.Any factors that increase the risk of QTc
prolongation or risk of arrhythmic events such as hypokalemia, 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 and cause Torsade de Pointes.
11. Hypertension uncontrolled by standard therapies (not stabilized to < 150/90
mmHg).
12. Contraindication to the administration of osimertinib.
13. Medical history of liver fibrosis/cirrhosis.
14. Past or current history of neoplasm other than NSCLC, except for curatively
treated non-melanoma skin cancer, in situ carcinoma of the cervix, benign
prostate neoplasm/hypertropia,or other cancer curatively treated and with no
evidence of disease for at least 5 years.
15. Medical history of difficulty swallowing, malabsorption, or other chronic
gastrointestinal disease, or conditions that may hamper compliance and/or
absorption of the tested product.
16. Major surgery within 28 days prior to Day 1 of study intervention.
17. Known human immunodeficiency virus positivity.
18. Known hypersensitivity to any of the study intervention ingredients.
19. Has not received an EGFR-TKI containing treatment directly prior to
enrollment into the study, ie, chemotherapy or checkpoint inhibitor treatment
with/without vascular endothelial growth factor inhibitors either in
monotherapy or in combination are allowed, if these treatments do not represent
the most recent treatment lines prior to enrollment
20. Prior treatment with other agents targeting the Hepatocyte Growth Factor
(HGF)/MET pathway such as crizotinib, capmatinib, savolitinib, foretinib,
glesatinib, cabozantinib, merestinib, onartuzumab, rilotumumab, emibetuzumab,
and ficlatuzumab.
21. Participants currently receiving (or unable to stop use at least 1 week
prior to receiving the first dose of study intervention) medications or herbal
supplements known to be potent inducers of CYP3A4.
22. Participation in another interventional clinical study (except those
participants who were solely involved in other studies where the
investigational product was osimertinib in the first-line of therapy)
within the 30 days prior to randomization/first dose.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-001538-33-NL |
| ClinicalTrials.gov | NCT03940703 |
| CCMO | NL70294.056.19 |